The ChEMBL-og - Open Data For Drug Discovery

New Drug Approvals 2012 - Pt. III - Axitinib (INLYTA®)

2012-01-31T07:49:00.000Z

ATC Code: L01XE17

Wikipedia: Axitinib

On Jan 27th 2012, the FDA approved Axitinib (also known as AG-13736, trade name: Inlyta), a kinase inhibitor, for the treatment of advanced renal cell carcinoma after failure of a first line systemic treatment.

Renal Cell Carcinoma (RCC) is a cancer of the lining of proximal convoluted tubules, the tiny tubes through which the blood is filtered, in the kidney. It is the most common type of kidney cancer in adults and is responsible for 80% of all kidney cancers (Cancer Research UK). Over 270,000 new cases of kidney cancers are diagnosed every year and the numbers are on the rise (CRUK)

Axitinib is a tyrosine kinase inhibitor, inhibiting all subtypes of the Vascular Endothelial Growth Factor Receptor (VEGFR), VEGRF1 (Uniprot:P17948; ChEMBL1868 ; canSAR), VEGFR2 (Uniprot:P35968; ChEMBL ; canSAR) and VEGFR3 (Uniprot:P35916 ; ChEMBL; canSAR).
VEGFRs are single-pass membrane receptors that have multiple extracellular Immunoglobulin-like domains involved in growth factor binding (the ligand is VEGF); and an intracellular Tyrosine Protein Kinase catalytic domain (pfam:PF07714). Axitinib inhibits this kinase domain ( rough boundaries shown as sequence alignment)

(PDB code: 1y6b; VEGFR2 kinase catalytic domain)


P17948  827   LKLGKSLGRGAFGKVVQASAFGIKKSPTCRTVAVKMLKEGATASEYKALMTELKILTHIGHHLNVVNLLGACTKQGGPLM  906
P35968  834   LKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLM  913
P35916  845   LHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKILIHIGNHLNVVNLLGACTKPQGPLM  924

P17948  907   VIVEYCKYGNLSNYLKSKRDLFFLNKDAALHME-PKKEKMEPGLEQGKKP-RLDSVTSSESFASSGFQEDKSLSDVEEEE  984
P35968  914   VIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFR-QGKDYVGAIPVDLKR--RLDSITSSQSSASSGFVEEKSLSDVEEEE  990
P35916  925   VIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRFRAMVELARLDRRRPGSSDRVLFARFSKTEGGARRAS----PDQE  1000

P17948  985   DSDGFYKEPITMEDLISYSFQVARGMEFLSSRKCIHRDLAARNILLSENNVVKICDFGLARDIYKNPDYVRKGDTRLPLK  1064
P35968  991   APEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLK  1070
P35916  1001  A-EDLWLSPLTMEDLVCYSFQVARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLK  1079

P17948  1065  WMAPESIFDKIYSTKSDVWSYGVLLWEIFSLGGSPYPGVQMDEDFCSRLREGMRMRAPEYSTPEIYQIMLDCWHRDPKER  1144
P35968  1071  WMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQR  1150
P35916  1080  WMAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELATPAIRRIMLNCWSGDPKAR  1159

P17948  1145  PRFAELVEKLGDLLQANVQQDGKDYI--PINAILTGNSGFTYSTPAFSEDFFK-ESISAPKFNSGSSDDVRYVNAFKFMS  1221
P35968  1151  PTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKF--------HYDNTAGISQ  1222
P35916  1160  PAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQ-SSEEGSFSQVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPG  1238

P17948  1222  L----------ERIKTFEELL---PNATSMFDDYQGDSSTLLASPMLKRFTWTDSKPKASLKIDLRVTSKS----KESGL  1284
P35968  1223  YLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTL---EDRTKLSPSFGGMVPSKS----RESVA  1295
P35916  1239  CLARGAETRGSSRMKTFEEFPMTPTTYKGSVD-NQTDSGMVLASEEFEQI---ESRHRQESGFSCKGPGQNVAVTRAHPD  1314

P17948  1285  SDVSRPSF-CHSSCGHVSEGKRRFTYDHAELER----KIACCSPPPDY----NSVVLYSTPPI  1338
P35968  1296  SEGSNQTS--GYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV  1356
P35916  1315  SQGRRRRPERGARGGQ-------VFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY-------  1363

Axitinib (Trade name: Inlyta®; IUPAC= N-methyl-2-[3-((E) 2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide; Canonical SMILES: CNC(=O)c1ccccc1Sc2ccc3c(\C=C\c4ccccn4)n[nH]c3c2 ; InChIKey=RITAVMQDGBJQJZ-FMIVXFBMSA-N); (ChEMBL1289926; canSAR)
It has the molecular formula C22H18N4OS. Its molecular weight is 386.47, and has an AlogP of 4.49. Following single oral 5-mg dose administration, the median Tmax ranged between 2.5-4.1 hours.The mean oral bioavailability is 58%. Axitinib is highly bound (>99%) to human plasma proteins. The plasma half life (T_1/2varies between 2.5 and 6.1 hours. It is metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.

Full prescribing information can be found here.
Axitinib (Inlyta) is a product of Pfizer

Estimates of Clinical Attrition

2012-01-29T18:12:00.001Z

I am the world's best procrastinator, always putting things off - today I've actually got a whole bunch of stuff done - the motivator for this was promising myself that once I'd done a big pile of stuff, I'd write something for the blog. Yes, I'm weird, but I find that writing this stream os ASCII characters on your screen right now, makes me think about the way to explain things to others, and also makes me ask the important question 'is this likely to be of any interest to anyone?'.

Anyway, here's a toy analysis - Clinical attrition rates are the subject of a lot of analyses, the most rigorous ones usually involve the survey of a set of large pharma companies, and then analysis of the attrition. This is simple, and has led to various estimates of around 1:10 survival from phase 1 to launch to a 1:20 number. So 90 to 95% of compounds entering clinical trials fail, success probability is about 0.05. My hunch is that this is an underestimate - Logically, large pharma should be the best at pushing things through development, and if analysis is restricted to this best-in-class subset, surely the attrition of the remainder should be higher. Let's do a back of the envelope calculation, and let the data speak - or at least point us to the data we actually need to put together in order to do it right. I don't have time to point to some references for these numbers, that is for another day; remember, I'm only half way through my list of urgent things to do, or I will be in trouble.....

So, picking up on the discussion of kinase inhibitor attrition recently - about 20% of the USAN named compounds make it to market - this is roughly the same as the non-kinase set of drugs (data not shown). So this is 1:5 attrition (or 0.2 probability). Now, for the kinases, we have a pretty good set of data for all compounds that have entered clinical trials, and the ratio of non-USAN to USAN compounds is about 3:1, so using a steady state assumption (which is probably reasonable, data not shown, but the subject of a future post), gives a transition probability from entering clinical trials to non-proprietary name assignment of 0.25.

So overall, the attrition, from this small, but well characterised set is (0.2 * 0.25) which is 0.05, or 1 in 20. So things hang together quite well, and the number is sorta consistent with other analyses. Next some correlation with chemical properties.

Japanese Drug Approvals

2012-01-29T08:33:00.000Z

It's sometimes difficult to trace the approval process for drugs in 'foreign' countries - of course, foreign is relative, but nonetheless as a non-local it is difficult to know where to start. As an example, I tried a number of 'social media' approaches to find out about Chinese Drug non-proprietary naming - Quora, Google+ the ChEMBL-og and LinkedIn - LinkedIn was by far the best in terms of useful leads and information, often from 2nd or 3rd away links. Thanks to all that helped so far.

Anyway, here's a website in Japan which contains a definitive list of Japanese Drug Approvals, and which has sections in the English language to help non-Japanese readers/speakers.

It's the Pharmaceutical and Medical Devices Agency, Japan, website - http://www.pmda.go.jp/ with an English version at http://www.pmda.go.jp/english/

There are convenient, yearly approval summaries, in English - http://www.pmda.go.jp/english/service/list_s.html

Package inserts are here http://www.info.pmda.go.jp/info/iyaku_index.html (Japanese only).

As a general comment, I find the websites for the primary US and European drug approval agencies (www.fda.gov and www.emea.europa.eu) to be very complex to use, have unstable links (so things can move around and disappear), have no obvious site maps, or ways of retrieving data in a programmatic/hackamatic way - which given that these are obvious cases where opening up and ready availability of public/government data is surprising. The ability to link in to these sites is essential, and at the moment, can't be reliably done.

As an aside, there's a very good database in the UK - UK Medicines Information, which, unfortunately is only available to NHS employees, or other associated staff (presumably for licensing reasons?). However, a lot of the post-sign-in content is indexed in well known search engines - you just need to know what you are looking for ;)

New Drug Approvals 2012 - Pt. II - Ingenol mebutate (PICATO®)

2012-01-27T08:34:00.003Z

On Jan 23rd 2012 the FDA approved Ingenol mebutate gel for the topical treatment of actinic keratosis (AK). Ingenol mebutate (trade name: PICATO®, formally known as PEP-005) is a natural product derived from the euphorbia plant.

Actinic, or solar keratosis (Wikipedia; NIH; OMIM) is a pre-cancerous pigmented lesion on the skin, most commonly occurring in skin that has been frequently exposed to the sun. If left untreated, about 20% of cases transform into Squamous Cell Carcinoma.

Ingenol mebutate induces cell death in Actinic Keratosis. The precise targets responsible for the mechanism of action is not known, however, Ingenol derivatives (see e.g. CHEMBL346507) have been shown to have anticancer activities. Many of these derivatives have activity on several Protein Kinase C isoforms. Mechanistically Ingenol mebutate causes rapid lesion necrosis and also specific neutrophil-mediated, antibody-dependent cellular cytotoxicity

Ingenol mebutate (IUPAC: 2-Butenoic acid, 2-methyl-, (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-1a,2,5,5a,6,9,10,10a-octahydro 5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11-oxo-1H-2,8a-methanocyclopenta [a]cyclopropa[e]cyclodecen-6-yl ester, (2Z) - or (1aR,2S,5R,5aS,6S,8aS,9R,10aR)-5,5a-dihydroxy-4-(hydroxymethyl)-1,1,7,9-tetramethyl-11 oxo-1a,2,5,5a,6,9,10,10a-octahydro-1H 2,8a-methanocyclopenta[a]cyclopropa[e]cyclodecen-6 yl (2Z) 2 methylbut-2-enoate). Ingenol mebutate is the mebutate ester of ingenol, and is a natural product isolated from the plant Euphorbia peplos. Ingenol is a diterpene, and is part of a diverse super-family of bioactive natural products - including phorbol esters, Reseniferatoxin and Gnidimacrin. Specifically, Ingenol mebutate is a member of the Ingenane family of natural products, and contains a Bicyclo[4.4.1]undecane ring system with in – out stereochemistry. Ingenol esters found in Euphorbiaceae, and were traditionally used in the treatment of tumors, migraines, parasites, gingivitis, and also as purgatives.

Its molecular formula is C25H34O6; molecular weight is 430.5 Da. It is a clear gel provided in two concentrations: 0.015% and 0.05%. These contain 150 mcg and 500 mcg of ingenol mebutate, respectively. It is applied to the lesion and the immediately surrounding skin. Pharmacokinetic studies have shown that absorption into the bloodstream (systemic exposure) is undetectable.

Picato® is produced and marketed by Leo Pharma.

The full prescribing information can be found here.

Paper: Quantifying the Chemical Beauty of Drugs

2012-01-26T08:42:00.000Z

There's a really interesting paper just published in Nature Chemistry - 'Quantifying the chemical beauty of drugs' from the group of Andrew Hopkins up at Dundee. Links to the paper are here, and an associated opinion piece in Nature here.

We'll add these descriptors to a future release of ChEMBL....

%T Quantifying the chemical beauty of drugs
%A G.R. Bickerton
%A G.V. Paolini
%A J. Besnard
%A S. Muresan
%A A.L. Hopkins
%J Nature Chemistry
%V 4
%P 90–98
%D 2012
%O doi:10.1038/nchem.1243

Meeting: MGMS Cutting Edge Approaches to Drug Design, 26th April 2012

2012-01-26T06:31:00.000Z

Registration for the Cutting Edge Approaches to Drug Design (CEADD) 2012 meeting is now open. This meeting, organised by the MGMS, is the latest in a highly successful series of conferences, which have been held in collaboration with the RSC-MMG. The meetings are aimed at those who have an interest in the use of computational chemistry in drug discovery and development. This includes medicinal chemists, as well as structural biologists and cheminformaticians. The emphasis is on interdisciplinarity in drug discovery and also on evolving tools and techniques and their application in understanding biological systems.

CEADD2012 will be held on Thursday, 26th April, 2012, at the School of Oriental and African Studies in Russell Square, London. More details, including the list of speakers and information on how to register, can be found at the conference website (http://www.mgms.org/CEADD2012/index.html).

Joining the MGMS is even easier than ever, and it's cheap; so go on, support the field of molecular modelling!

Challenges of data integration

2012-01-25T08:57:00.000Z

Here is an example of why data integration across resources is hard - and hard at multiple levels. It's presented as an example of where things can trip up the unwary..... In 1999, the structure of carbonic anhydrases II and IV complexed to the approved drug brinzolamide were published. These structures gave insight into how the drugs bind their targets, and also selectivity. The coordinate set we''re specifically interested in here is 1a42. 3-D complexes of ligands with proteins are of incredible importance in many areas, not least in docking method/scoring function development.

In the original paper the structure is drawn as....

which is correct, and the same as found in wikipedia (Brinzolamide) and ChEMBL (CHEMBL220491). The structure in the PDB file however is something else, an isomer of brinzolamide - the IUPAC name of the ligand in the coordinate set is

(4R)-2-(2-ETHOXYETHYL)-4-(ETHYLAMINO)-3,4-DIHYDRO-2H-THIENO[3,2-E][1,2]THIAZINE-6-SULFONAMIDE 1,1-DIOXIDE

So instead of having the methoxy at the chain terminus there is an ethoxy, and the chain between the oxygen and the ring is one atom shorter - the oxygen has migrated one atom along. This is not brinzolamide, but it's called brinzolamide in the PDB entry (but the structure's wrong), and the paper (where the structure is right). The most likely explanation is that when the crystallographers built the topology file for the ligand they mistyped the atom name/element/whatever - this was a pain back then.

As a first question - what should PDB curators do here? Spot the error and fix the data, probably not, that's not the way that PDB works, but this post-loading, fixing and futzing around with the original data is common in other databases (e.g. ChEMBL). For me, this is the difference between an archive, an a curated resource.

The next level of ambiguity is where people try and extract the chemical structure from the PDB entry (for historical reasons there is no connection table in the PDB file); there's two general ways of doing this - 1) from the IUPAC name in the header, and 2) from the coordinates. Most workers have tackled the latter method, but working out the bonding from the coordinates is surprisingly hard to do completely correctly.

So what happens in this case? Well the AffinDB resource has this (AffinDB is a great resource for structure-based design and dockers).

So, two problems here, loss of stereochem off the ring (it is unambiguous in the 3D coords) and secondly the loss of the double bond for the thiophene - this has the side effect of introducing two new chiral centres into the molecule (so eight possible enantiomers, from the one defined structure used in the experiment). So the ligand, if converted to 3D, from the above structure could not recover the geometry as found in the database. Also the sulphonamide, which binds to the zinc in CAH will no longer be acidic (aryl sulphonamides are weakly acidic), and so the difference will have big differences in terms of inhibitor properties.

And what about PDBe? Well the structure there is this....

Which gets the double bond in the thiophene right, but introduces a spurious chiral centre at the sulphonamide nitrogen. This is quite a subtle case, since the nitrogen in a sulphonamide has a lot of sp³ character, and maybe one configuration is trapped in the crystal complex - but in solution, it will very rapidly invert and equilibrate - it is not a chiral centre.

In summary, this chain of events makes the data integration problem a hard one (for example if one wanted to query across ChEMBL, PDBe, AffinDB at least), and there are confounding statements on what the identity of a particular molecule is, and taking the PDB entry on face value would be confusing. So, data integration is hard! - 'Trust and Verify' is the mantra, but trust and verify names and synonyms even more.

Approvals and Attrition of Protein Kinase Inhibitors

2012-01-24T05:47:00.002Z

Protein kinases are one of the 'hot' families in drug discovery, and last year (2011) had the highest number of approvals for protein kinase inhibitors ever - 4, these being Vandetanib (Zactima), Crizotinib (Xalkori), Ruxolitinib (Jafaki) and Vemurafenib (Zelboraf). Some of these are real breakthrough medicines, offering seriously ill patients improvement of life/extended life in terminal diseases. 2011 also saw the assignment of 12 new INNs/USANs for protein kinase inhibitors - these will form the cohort of drugs from which future approvals will come. It's interesting to track the approval ratios, a comparison of input to output (numbers of INNs/USANs to the number of approvals). Of course, there are some challenges with applying a simple approach such as this, since there is a delay between USAN/INN assignment and approval, but this will probably only be a significant issue when there is a large increase/decrease in a particular year. We also know that the 'time constant' between USAN/INN assignment and approval is about 2-4 years for approved drugs, so on average, at steady state, things will balance out.

Anyway, here are some graphs of the numbers, they should make sense without further explanation. One of the reasons for writing this was that I was at a talk recently where kinase inhibitors were treated as 'blessed' during development, that is, that they suffered lower than average attrition during development - the approval ratio is converging at about 0.2 (remember this number (one in five) is roughly the fraction of phase IIb to market, certainly not overall clinical attrition). The plotted number (blue triangles with green line) is the ratio of the cumulative USAN number to the cumulative approved number for that particular year). To my eye, the data doesn't really support this 'blessed' view - so unless the time between USAN/INN assignment and approval is systematically longer for protein kinases than other drug types (and even then under a steady assignment/approval rate scenario that doesn't matter). However, based on the large jump in 2010 USAN assignment 2013-2014 should deliver a bumper crop of new kinase drugs.

Comments as always welcome in the blog comments.

A small update - some numbers...

Highest Trial Phase	Fraction with USAN
IV (launched)	1.00
III	0.97
II	0.34
I	0.07

The phase 1 include quite a few Chinese NNs (still trying to get to the bottom of the naming scheme for these), also cancer is a little odd in that there are a lot of Phase I/II combined trials, and so the ratio of Phase I to Phase II is a little unusual.

New Drug Approvals 2012 - Pt. I - Glucarpidase (VoraxazeTM)

2012-01-23T11:32:00.000Z

ATC code: V03AF09

The first FDA new drug approval of 2012 is Glucarpidase, approved on Jan 17th 2012. Glucarpidase (tradename: Voraxaze; formerly known as carboxypeptidase-G2 or CPG2) is a carboxypeptidase enzyme indicated for the treatment of toxic plasma methotrexate (MTX) concentrations (>1 umol/L) in patients with delayed MTX clearance due to impaired renal function.

MTX (ChEMBL: CHEMBL426) is an antifolate drug and is one of the most widely used anticancer agents. Unlike other anticancer agents, MTX can be safely administrated over a wide dose range. However, during treatment with high doses of MTX, patients may develop renal dysfunction. Since MTX is primarily cleared by renal excretion, this will lead to toxic levels of MTX. Glucarpidase acts by converting MTX to its inactive metabolites 2,4-diamino-N¹⁰-methylpteroic acid (DAMPA) and glutamic acid, providing thus an alternate route of elimination to renal excretion.

Glucarpidase (Uniprot: P06621) is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. The crystal structure of Glucarpidase is known (PDBe: 1cg2, homotetramer form).

>Glucarpidase
ALAQKRDNVL FQAATDEQPA VIKTLEKLVN IETGTGDAEG IAAAGNFLEA ELKNLGFTVT
RSKSAGLVVG DNIVGKIKGR GGKNLLLMSH MDTVYLKGIL AKAPFRVEGD KAYGPGIADD
KGGNAVILHT LKLLKEYGVR DYGTITVLFN TDEEKGSFGS RDLIQEEAKL ADYVLSFEPT
SAGDEKLSLG TSGIAYVQVN ITGKASHAGA APELGVNALV EASDLVLRTM NIDDKAKNLR
FNWTIAKAGN VSNIIPASAT LNADVRYARN EDFDAAMKTL EERAQQKKLP EADVKVIVTR
GRPAFNAGEG GKKLVDKAVA YYKEAGGTLG VEERTGGGTD AAYAALSGKP VIESLGLPGF
GYHSDKAEYV DISAIPRRLY MAARLIMDLG AGK

The recommended dosage of Glucarpidase is a single intravenous injection of 50 Units/kg.

Glucarpidase has a volume of distribution (Vd) of 3.6 L, a systemic clearance (CL) of 7.5 mL/min and an elimination half-life (t1/2) of 5.6 hours.

The full prescribing information of Voraxaze can be found here.

The license holder is BTG international Inc.

Course - Resources for Computational Drug Discovery

2012-01-19T16:08:00.000Z

A heads up on a course being held on campus here in early July - the joint EMBL-EBI and Wellcome Trust Resources for Computational Drug Discovery. The speakers are excellent, but check out the early material online for the course here. Based on previous courses, please book early to avoid disappointment ;)

EBI Open Day - 1st March 2012

2012-01-17T05:06:00.000Z

The EMBL-EBI is holding one of its regular Open Days on March 1st 2012 - details are at www.ebi.ac.uk/training/openday. These are always really fun events, and give a great insight into life, careers, and activities at our work. The deadline for registration is February 1st 2012.

USAN Watch - January 2012

2012-01-14T04:30:00.003Z

The USANs for January 2012 have just been published.

USAN	Research Code	Structure	Drug Class	Therapeutic class	Target
arhalofenate	MBX-102, JNJ-39,659,100		synthetic small molecule	therapeutic	PPAR-gamma
bitopertin	Ro-4917838		synthetic small molecule	therapeutic	GlyT1
naldemedine	S-297,995		natural product-derived small molecule	therapeutic	peripheral opioid receptors
pateclizumab	RG-7416, PRO-283698, MLTA-3698A		mab	therapeutic	lymphotoxin alpha
pictilisib	GDC-0941, RG-7321		synthetic small molecule	therapeutic	PI3K, mTor
tivozanib, tivozanib hydrochloride	AV-951, Kil-8951		synthetic small molecule	therapeutic	VEGFR

Update: Fixed research code for Pactelizumab - thanks to Robert Jones (details in the comments).

Paper: Global Analysis of Small Molecule Binding to Related Protein Targets

2012-01-13T18:24:00.000Z

Many drugs are small molecules that specifically bind to proteins involved in disease related processes. In this way, drugs modulate the function of a targeted protein and ultimately the process causing the disease. The development of drugs crucially relies on assays that measure the potency of the effect a small molecule exerts on its protein target. We compared the potencies of small molecules measured for human proteins and the corresponding (orthologous) protein in rat. Our results suggest that, after subtraction of statistical noise, most human proteins show equivalent potency for small molecule binding as their orthologs in rats. However, we identified a small number of exceptions to this rule, for example the histamine H3 receptor, a protein of the central nervous system. We also compared the potency of small molecules measured against a human protein and another member of the same protein family. In drug development it is often desired to target a protein selectively over other related proteins. The observed differences were generally greater than the statistical noise, indicating that most of the small molecules in our study have some degree of selectivity within protein families.

Link to the paper is here.

%A F.A. Krueger
%A J.P. Overington
%T Global Analysis of Small Molecule Binding to Related Protein Targets
%D 2012
%V 8
%P e1002333
%J PLoS Comput. Biol.
%O doi:10.1371/journal.pcbi.1002333

Anyone know anything about Non-Proprietary Drug naming in China?

2012-01-07T07:29:00.000Z

There are a comparatively large number of Chinese company invented drug entering clinical trials now - these are typically assigned USAN/INN looky-likey names, and seem to obey stem naming conventions. Does anyone know how these are assigned, is there an equivalent of USAN in China, where does the data get published, etc.?

As specific examples of these, there are a set of kinase inhibitors - Epitinib (EGFR), Flumatinib (ABL1), Fruquintinib (VEGFR), Icotinib (EGFR), Sulfatinib (VEGFR FGFR), Volitnib (MET).

I've also asked this question on Quora - I'll post any replies there in the comments section here.

Update: To be clear, I have no interest in the commercial import/export of drug substances into or out of China, I'm only interested in the name assignment process.

Talk - Alex Tropsha - Many Challenges and Some Solutions for Modeling Chemical Genomics Data: navigating structure – in vitro – in vivo response data space

2012-01-06T09:05:00.003Z

Welcome back after the holiday break!

We have a small informal seminar on campus, on Tuesday 17th January 2011 from Alex Tropsha from UNC, the talk will be titled “Many Challenges and Some Solutions for Modeling Chemical Genomics Data: navigating structure – in vitro – in vivo response data space".

If you are interested in attending from off campus - I will need to register you with security - so mail me.

Update: The seminar will be at 2pm in seminar room C202 (shared facilities). (Mail to arrange access for off campus attendees though!

Update 2: Please note - we cannot provide online access to the talk. Sorry.

Omics and Personalised Healthcare - February 2012

2011-12-21T11:25:00.001Z

We're speaking at the forthcoming EMBL Conference on Omics and Personalised Healthcare in Heidelberg, held 16th to 18th February 2012. We'll present some of our recent work on pharmacogenetic variation, and some strategies on both data-mining and some of the implications for drug discovery.

Three ChEMBL talks at the March ACS in San Diego

2011-12-17T09:51:00.001Z

A number of the ChEMBL team will be at the ACS in San Diego next March - we'll be giving a couple of talks - one is one drug safety (jpo) one is on peptide SAR analysis and design (Patricia Bento) and the final one is on UniChem (Jon Chambers). So hopefully see you there!

We'll be spending some time in the lab of one of our close collaborators - Mike Gilson at UCSD, but we're happy to meet up with others, give talks, training, etc. as time and travel schedules permit. So if you're interested in this, get in touch.

Update: Fixed post, to reflect three accepted talks.

PAPER ID: 20839
PAPER TITLE: "Drug combinations to reduce adverse drug reactions and improve intrapatient differences in response"
DIVISION: CINF: Division of Chemical Information
SESSION: Systems Chemical Biology and Other 

PAPER ID: 22715
PAPER TITLE: "UniChem: A prototype unified chemical structure cross-referencing and identifier tracking system"
DIVISION: CINF: Division of Chemical Information
SESSION: InChI Symposium

PAPER ID: 15760
PAPER TITLE: "Comprehensive analysis of explored and available physicochemical space for alpha-amino acids"
DIVISION: ORGN: Division of Organic Chemistry
SESSION: Peptides, Proteins, and Amino Acids

Kinase SARfari ver.5.0 Released

2011-12-16T16:58:00.002Z

We would like to announce the release of new version Kinase SARfari. The latest version has been updated using the chembl_12 data, which contains:

Bioactivity datapoints: 503041 (+15%)
Compounds: 54189 (+6%)

Various dumps of the data from Kinase and GPCR SARfari are also downloadable from the download page.

Of course, we welcome feedback from our users!

Spotfire DecisionSite replacement

2011-12-15T17:31:00.001Z

We used to use Spotfire DecisionSite for data visualisation, and liked it a lot - we've just found out there are some pretty major changes to the licensing; and are now looking for alternatives if we can't work out a way forward. So, any suggestions for good data exploration tools, preferably with some sort of chemistry capabilities. Ideally they would run natively on Mac OsX.

Ideas in the comments please.....

Christmas is coming, the goose is getting fat, must be the time to register for TACBAC!

2011-12-13T16:02:00.002Z

Rough Breakdown of Drug Classes for 2011

2011-12-09T12:47:00.001Z

Here's the equivalent view of drug approvals for 2011 so far - pretty similar picture in terms of the distribution of molecule classes - but remember this set of drug approvals, got their USANs assigned, on average about 3 to 4 years ago, so the sets are not strictly comparable, and of course, suffer from small absolute numbers....

Rough breakdown of USAN classes for 2011

2011-12-09T12:18:00.001Z

The 2011 set of USANs is almost complete, there are 114 of them, but some of these are salts of others, so the total number of distinct potential new drugs is smaller - actually 87 - this is smaller number that previous years. The breakdown by molecule class is quite interesting - remember this set comprise potential future approved drugs, and so, depending on the attrition within each set, the drugs of about three or four years time will look like these.

Small molecules still dominate the set, with almost three quarters of USANs in this class - biologicals are just over one quarter of the cohort.

By rough breakdown, I mean just this, I got out a pencil and a few printed lists and tallied them up - a bigger and better controlled analysis will be posted later.

USAN Watch - December 2011

2011-12-07T18:43:00.001Z

The USANs for December 2011 have just been published.

USAN	Research Code	Structure	Drug Class	Therapeutic class	Target
elotuzumab	BMS-901608		monoclonal antibody	therapeutic	CD-319

GPCR SARfari Ver.2.0 Released

2011-12-07T16:28:00.001Z

We would like to announce the release of new version GPCR SARfari. There are many changes to the interface, large increase of data and new functions including GPCR PDB & 3D Model Structures. The model structures were generated for all the GPCR sequences in the database using the latest GPCR PDB structures and the well-considered alignment. You can see & download the models on the protein report page. This version includes:

https://www.ebi.ac.uk/chembl/sarfari/gpcrsarfari/

• Updated assays, activities and compounds from chembl_11
   - Bioactivity datapoints: 904,571 (+358,104)
   - Compounds: 142,069 (+23,235)
   - Protein structures: 89 unique PDB structures
• Added GPCR 3D model viewer
• Added drug icons into the interface
• Added links to ChEMBL Target, Document and Assay Report Cards
• Unified SARREGNO to CHEMBL ID (also Assay & Doc ID)
• Renamed old sources (drugstore & candistore)

The SARfari's compound, activity and protein data are also downloadable from the web site: https://www.ebi.ac.uk/chembl/sarfari/gpcrsarfari/downloads

Happy ChEMBLmas!!

2011-12-07T11:57:00.001Z

As part of our tradition of making Xmas seasonal eCards to all our users - above is the December 2012 card. For the geeky amongst you, there may be an Easter Egg in the image file....

Conference: Advances in Protein-Protein Interaction Analysis and Modulation

2011-12-07T09:27:00.001Z

Registration is now open for a really interesting EMBO Workshop on the modulation of protein-protein interactions (ppi's). We're speaking, and will present some new stuff on annotation of ChEMBL with interacting domains, and a sort of classification of these into protein-protein interfaces (see some previous blog posts for some further details on this).

The meeting is in the beautiful French harbour town of Roscoff - the traditional home of Onion Johnnies - well, I love onions, and my name is John, and I'll be there!

Amgen Scholars Program

2011-12-06T10:19:00.001Z

Due to a lot of wasted time in the past, my lab does not host or support applications to the Amgen Scholars Program, so please do not apply to us!

Papers: MIRIAM and Identifiers.org

2011-12-06T08:52:00.001Z

The NAR Database Issue is currently in full flow, and there are many excellent articles; one important one for ChEMBL is this paper from the group of our good friend Nicolas Le Novere, at the EBI. It addresses a really important problem in biological and chemical data integration through the generation of unique and stable identifiers for records in a data collection – these are MIRIAM identifiers (MIRIAM is an acronym for Minimum Information Required in the Annotation of Models Registry (http://www.ebi.ac.uk/miriam). Identifiers.org is a new service (http://identifiers.org) that is built upon the information stored in the MIRIAM Registry and which provides directly resolvable identifiers, in the form of Uniform Resource Locators (URLs). Resources such as this are essential components for ad hoc, distributed queries across disparate data sources, and a core component for semantic web development.

A link to the free pdf of the paper is here.

ChEMBL is in identifiers.org, give it a go!

%J Nucleic Acids Research
%D 2011
%O doi:10.1093/nar/gkr1097
%T Identifiers.org and MIRIAM Registry: community resources to provide persistent identification
%A N. Juty
%A N. Le Novere
%A C. Laibe

MIPTEC 2012 and EMBO Chemical Biology 2012

2011-12-05T09:02:00.001Z

A quick post to say that two of the best conferences in Europe next year are coordinating speakers and schedules for the Drug Discovery sessions to allow a really great line-up of talks and speakers, and to allow the best use of your (always too small!) travel budgets for conference attendance in these economically tough times. More later, but pencil both conferences into your diary now!

MIPTEC 2012 - September 24th to 27th 2012, Basel, Switzerland
EMBO Chemical Biology - September 26 to 29th 2012, Heidelberg, Germany.

Cape Town

2011-12-03T14:27:00.001Z

I've just spent a great week in Cape Town, at UCT, visiting the lab of Kelly Chibale; where there's lots of activity in academic drug discovery, and also at the Institute of Infectious Disease and Molecular Medicine. My first time in Africa, and it won't be my last!

3,788 Thank yous!

2011-12-02T04:41:00.001Z

So a big and heart-felt three thousand, seven hundred and eighty eight 'Thank Yous' to all the benevolent donors to the EBI Movember Team - The Bioinformoustachians. It was a lot of fun, the place is a lot hairier now, and there are more smiles on faces than at the start of the month.

Mission accomplished by our International (hair)peace keeping force - The Victoria and George Crosses (respectively) are awarded to Francesco Iorio (sgt. 8th Italian light foot) and Remco Loos (cpl. 4th Dutch commando) for their epic struggle and hand-to-hand combat for first place in the fund-raising league table, and a 'mention in despatches' is presented to Nicolas Le Novére (lt. 1st French prancers) for being the 'Top Gun' amongst the faculty. The platoon is now returning home, and will soon be changing back into 'civvies' (much to the relief of their partners and family).

If any other large science data centres want to make a fight of it for Movember 2012 - bring it on, we are waiting!

PS, it's still not too late to donate (up to December 8th 2011) at http://mobro.co/ebi

ChEMBL 12 Released

2011-12-01T14:57:00.003Z

We are pleased to announce the release of ChEMBL_12. This latest version of the ChEMBL database contains:

1,222,969 compound records
1,077,189 distinct compounds
596,122 assays
5,654,847 bioactivities
8,703 targets
43,418 documents
7 data sources

This release includes updates to the manually extracted Medicinal Chemistry literature, a number of published ADMET datasets (for metabolic enzymes and various transporters), updates to OrangeBook drug approvals and a partial update from PubChem BioAssay. ChEMBL_12 also contains a new deposited dataset of Malaria liver-stage screening data from Novartis-GNF (for more details on this dataset, please see ChEMBL-NTD website and the recent publication in Science).

Please refer to the ChEMBL_12 release notes for a more detailed description of all changes included in this release.

You can download the data from the ChEMBL ftpsite: ftp://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/latest/

Paper: Drug Repurposing from an Academic Perspective

2011-11-28T11:20:00.001Z

There is a great paper in Drug Discovery Today: Therapeutic Strategies reviewing experience in a large number of drug repurposing experiments performed at one institute - the University of New Mexico. There is a lot of interest in the potential of drug repurposing, many papers discussing various theoretical approaches, discussion of IP, etc, but relatively few present real-world, worked examples. The well-known examples tend to be the successful ones, and have now become almost cliches - Sildenafil and Thalidomide for example. Discussion of the challenges encountered is far less common, and this paper covers a portfolio of projects, identified by a mix of empirical broad screening, virtual screening, or hypothesis-led research - a summary of each of them w.r.t. their status and progress is then outlined - finally some conclusions are presented - the most valuable and sobering ones being the limiting factors.

A further feature of the paper is the sheer complexity (and cost) of this sort of work if tackled seriously with a genuine translational science approach, as opposed to a list of hits from an in vitro/virtual screen, that are proposed for testing.

For those of you dying to know the 'punchlines' on the current challenges (as one might expect, data availability is a major component behind all of these), these are:

Dosing and safety
Lack of integration with pharmaceutical sciences and toxicology
Appropriate intellectual property coverage

%T Drug repurposing from an academic perspective
%J Drug Discovery Today: Therapeutic Strategies
%A T.I. Oprea
%A J.E. Bauman
%A C.G. Bologa
%A T. Buranda
%A A. Chigaev
%A B.S. Edwards 
%A J.W. Jarvik
%A H.D. Gresham
%A M.K. Haynes 
%A B. Hjelle 
%A R. Hromas
%A L. Hudson
%A D.A. Mackenzie
%A C.Y. Muller
%A J.C. Reed
%A P.C. Simons
%A Y. Smagley
%A J. Strouse
%A Z. Surviladze
%A T. Thompson
%A O. Ursu 
%A A. Waller
%A A. Wandinger-Ness
%A S.S. Winter
%A Y. Wu
%A S.M. Young
%A R.S. Larson
%A C. Willman
%A L.A. Sklar
%O doi:10.1016/j.ddstr.2011.10.002

Google Citation Wordcloud

2011-11-27T08:39:00.001Z

I am really schizophrenic over the importance and relevance of citations statistics - of course there are always great reasons why your citations are lower than they should really be, and why your peers citations are higher than they should be. However, it is the case that they are a necessary evil as an academic, and human psychology draws us in, like a single-minded light-obsessed moth to a candle flame, to comparing ourselves against each other in various ways. I used to use Thomson Reuter's Web of Science for this, but the tools to manage a personal list are odd and clunky, and the system seems to have recently been ported to an old 80286 with 4MB of RAM (the spec of my first personal Unix machine, with a built-like-a-tank American Megatrends Inc motherboard. Ahhh good-times with "Uncle Mark" and "Spock The Vulcan"); To counter this frustration, Google Scholar Citations has recently gone public, and it is great, easy tools to validate and merge publications, the ability to have private or public views on the data - the only thing that seems snafu'd is the adding of a link to a home page (it just replies that I need to add a valid link). I won't post a link to my citation page (it is public though), since they are, between you and me, shameful, since I wasn't able to publish the best stuff while I was in industry (damn, there I go again!).....

Anyway, Google Scholar Citations can be programmed against, and Google Plus alerted me to an R script that can draw a word cloud for co-authors and key-words for a given author.

The R source is here, but you may need to install some other packages to get it to run. The image above is the word cloud for all of my publishing career - all 23 years of it. It's interesting to see the protein structure and comparative modelling stuff as the strongest concepts, but this has also been the basis of a lot of the more recent work, including the database stuff. At the end of the day, for me, 3-D structure is the most satisfying and stimulating way to thing about ligand data and design.

I must admit I didn't know that R did word clouds, so expect a few more gibberish filled blog posts while I play with this!

PS If this post sounds like a eulogy and advert for Google, it most definately isn't, since they recently decided to shut down their University Research Programme to Google Search :( boo. hiss.

Crimewatch?

2011-11-25T10:34:00.001Z

http://mobro.co/ebi

UniChem - An EBI compound structure cross-referencing resource

2011-11-25T09:51:00.001Z

We have faced for some time some issues with compound integration with ChEMBL - specifically the loading of compound sets into ChEMBL for cross referencing, between for example, ChEBI, PDBe compounds, etc. The ChEMBL update cycle is relatively slow with respect to some other resources, and there is inevitable thrash with compounds not being present, especially for exciting new data. Without doing something different for compound integration, we were starting to face a scenario where we had a compound table with many millions of compounds without any bioactivity data, and following this the inevitable slowdown in searching, etc.

We also had some issues facing us about curation of other people's primary data, changing compound structures, or their rendering, etc.

So, we decided to set up an external system to resolve cross-references between various databases. This is a very simple Standard InChI lookup, containing compounds from resources such as ChEMBL, ChEBI, PDBe, DrugBank, KEGG, BindingDB, PubChem, and so forth. UniChem can also handle versioning of the contained resources. We will be migrating various components of the current ChEMBL interface across to use web services on UniChem, this way, the cross links will always be fresh and correct, and we can focus on curation and optimisation of ChEMBL content. There are some other resources, like ZINC, STITCH, and ChemSpider, for example, that would be great to integrate, if we can get hold of the required data.

The easiest way for us to handle deposition into UniChem is for us to take an ftp: feed of a simple table of resource_id, standard_InChI, and standard_InChI_key.

At the moment, UniChem sits behind our firewall, but if people want to have a play, let us know.

We will write something more specific and detailed, but would welcome thoughts of whether this resolver should be externally facing, and what other resources would be good to integrate?

The image above may or may not be the UniChem logo.

ChEMBL Widgets Update

2011-11-24T16:59:00.005Z

We have made a couple of minor updates to the ChEMBL widgets, which include:

A new widget has been created, which displays the bioactivity results shared between a ChEMBL compound and a ChEMBL target
A new scaling parameter allows you to vary the size of the widget
A more informative message is provided when widget has no data to display

More details can be found here

Further Depositions to ChEMBL-NTD

2011-11-23T20:39:00.001Z

We're delighted to announce the availability of three distinct new datasets on the ChEMBL-NTD portal, available for download, reuse, etc.

These are:

Novartis-GNF Malaria Liver Stage dataset (associated with this Science publication) (Plasmodium falciparum).
DNDi Human African Trypanosomiasis (HAT) dataset (Trypanosoma brucei)
DNDi Chagas Dataset (Trypanosoma cruzi).

Further details of the assays and compounds are to be found on the ChEMBL-NTD portal. The data will be integrated and loaded into a future version of ChEMBL, as well as the direct data download links. Once more, we thanks the depositors, DNDi and Novartis-GNF, for their benevolence and commitment to Open Science.

The associated publication for the Novartis-GNF dataset is:

%T Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery
%A S. Meister
%A D.M. Plouffe
%A K.L. Kuhen
%A G.M.C. Bonamy
%A T. Wu
%A S.W. Barnes
%A S.E. Bopp
%A R. Borboa
%A A.T. Bright
%A J. Che
%A S. Cohen
%A N.V. Dharia
%A K. Gagaring
%A M. Gettayacamin
%A P. Gordon 
%A T. Groessl 
%A N. Kato
%A M.C.S. Lee
%A C.W. McNamara
%A D.A. Fidock
%A A. Nagle
%A T-g Nam 
%A W. Richmond
%A J. Roland
%A M. Rottmann
%A B. Zhou
%A P. Froissard 
%A R.J. Glynne
%A D. Mazier 
%A J. Sattabongkot
%A P.G. Schultz
%A T. Tuntland
%A J.R. Walker 
%A Y. Zhou
%A A. Chatterjee
%A T.T. Diagana 
%A E.A. Winzeler
%J Science
%D 2011
%O DOI:10.1126/science.1211936

Interest in Links to Patents From Structures in ChEMBL

2011-11-23T07:30:00.001Z

We are exploring establishing links from the ChEMBL compounds to patents. The implementation can have two basic routes....

Links from the interface to patents (simple and quick to do now we have UniChem).
Patent uri's in the database itself (more complex, and more difficult to keep up to date, but arguably more useful).

So to help our planning for next year, comments, wishes are most welcome....

New Drug Approvals 2011 - Pt. XXXI Asparaginase Erwinia chrysanthemi (ErwinazeTM)

2011-11-22T09:48:00.001Z

ATC code: L01XX02

On November 18, the FDA approved asparaginase from Erwinia chrysanthemi for the treatment of patient with acute lymphoblastic leukemia (ALL) who have become allergic to the E. coli asparaginase that is conventionally used for the treatment of ALL patients.

ALL is a cancer of the white blood cells and can be fatal within weeks from the onset of the disease if it is left untreated. In ALL, there is an unproportional increase in the population of immature white blood cells, which crowd out functional immune cells as well as red blood cells and platelets, and in advanced stages of the disease infiltrate into tissues and organs, most frequently liver, spleen and lymph nodes. The symptoms of ALL in its initial stages are fatigue, anemia, frequent infections and fever as well as breathlessness and prolonged bleeding. ALL is caused by DNA damage and associated with exposure to radiation and cancerogenic chemicals. There are a number of typical chromosomal translocations, the most frequent in adults with ALL is the so called Philadelphia chromosome, where a translocation of chromosomes 9 and 22 results in the formation of the fusion gene bcr-abl (CHEMBL1862). Treatment of ALL is usually encompasses the three phases i) remission induction, which aims to quickly kill off 95% of the cancerous cells, ii) consolidation to further reduce the tumor burden and iii) maintenance with the aim to prevent a relapse caused by stray surviving leukemic cells.

Aspariginase is part of the remission induction regimen and used in combination with other cytostatic and cytotoxic drugs including prednisolone (CHEMBL131), dexamethasone (CHEMBL384467) , vincristin (CHEMBL303560) and daunorubicin (CHEMBL178). Asparaginase is an enzyme (EC 3.5.1.1) that catalyzes the hydrolysis of asparagine (CHEBI:17196) to aspartic acid (CHEBI17053) as shown below. Unlike healthy body cells, leukemic cells rely on the presence of extracellular asparagine for protein metabolism and survival, hence the beneficial effect for ALL patients. Conventionally, asparaginase for he treatment of ALL is derived from the bacterium Escherichia coli (corresponds to Uniprot:P00805) but some patients (estimated 10-15%) become allergic to this enzyme. For these patients, the ortholog from the bacterium Erwinia crysanthemi (Uniprot-Id P06608) is available to replace the untolerated treatment.

Asparaginase catalyzes the hydrolysis of asparagine to aspartic acid.

Asparaginase Erwinia crysanthemi is a tetrameric enzyme composed of four identical subunits each weighing about 35kDa. The crystal structures of many asparaginase enzymes are known, including that of the closely related protein from Erwinia carotovora (PDBe:2jk0)

The recommended dosage is 25.000 International Units/m² (International Units compare biological activity relative to an arbitrary amount of the active ingredient, square meter refers to body surface) three times a week. The route of administration is intramuscular injection.

The pharmakokinetic paramaters of Erwinaze were not determined in clinical trials, serum concentrations greater than 0.1 International Units/mL were reached by all patients within 72 hours of the third injection of aspariginase Erwinia chrysanthemi.

Side effects reported in the study include serious hypersensitivity reactions, pancreatitis, glucose intolerance, thrombosis and hemorrhage.

Asparaginase Erwinia chrysanthemi is marketed in the US by Eusa Pharma under the trade name Erwinaze. In a number of other countries, it is available under the name Erwinase.

Package information can be found here.

New Drug Approvals 2011 - Pt. XXX - Aflibercept (EyleaTM)

2011-11-21T10:38:00.020Z

ATC code (partial): S01LA

On November 18th 2011, the FDA approved Aflibercept (trade name: Eylea; Research Code: AVE-0005, also known as VEGF Trap), a recombinant fusion protein indicated for the treatment of patients with neovascular (wet) age-related macular degeneration (AMD).

AMD is an eye condition which usually occurs in older patients and affects the macula area of the retina, causing loss of vision and eventually blindness. In particular, wet AMD is characterised by an abnormal growth of new blood vessels (neovascularisation) behind the retina. This originates from an abnormal activation of angiogenesis, by the vascular endothelial growth factor-A (VEGF-A; ChEMBL: CHEMBL1783; Uniprot: P15692) and the placenta growth factor (PlGF; ChEMBL: CHEMBL1697671; Uniprot: P49763), of the vascular endothelial growth factor receptors VEGFR-1 (ChEMBL: CHEMBL1868; Uniprot: P17948) and VEGFR-2 (ChEMBL: CHEMBL279; Uniprot: P35968), two receptor tyrosine kinases present on the surface of endothelial cells. This leads to abnormal increased permeability, scarring and possibly to the loss of fine-resolution central vision. Aflibercept acts as a soluble 'decoy' receptor that binds VEGF-A and PlGF and thereby inhibits the binding and activation of the VEGFR-1 and VEGFR-2 receptors.

Aflibercept is a recombinant fusion protein that incorporates portions of extracellular domains of the human VEGFR-1 (containing Ig-like C2-type 2 domain fragment; Uniprot: P17948|151-214|) and VEGFR-2 (containing Ig-like C2-type 3 domain fragment; Uniprot: P35968|224-320|) fused to the Fc portion of human immunoglobulin G1 (IgG1). Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kDa (115 kDa with glycosylation).

>Aflibercept
SDTGRPFVEM YSEIPEIIHM TEGRELVIPC RVTSPNITVT LKKFPLDTLI PDGKRIIWDS
RKGFIISNAT YKEIGLLTCE ATVNGHLYKT NYLTHRQTNT IIDVVLSPSH GIELSVGEKL
VLNCTARTEL NVGIDFNWEY PSSKHQHKKL VNRDLKTQSG SEMKKFLSTL TIDGVTRSDQ
GLYTCAASSG LMTKKNSTFV RVHEKDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR
TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN
GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS
DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH
YTQKSLSLSP G

Other therapies to treat AMD are available on the market and these include Verteporfin (ChEMBL: CHEMBL1200573; approved in 2000; trade name Visudyne), Pegaptanib sodium (ChEMBL: CHEMBL1201421; approved in 2004; trade name Macugen) and Ranibizumab (ChEMBL: CHEMBL1201825; approved on 2006; trade name Lucentis).

Aflibercept recommended dosage is 2 mg administrated by intravitreal (into the eye cavity) injection every 4 weeks for the first 12 weeks, followed by 2 mg via intravitreal injection once every 8 weeks.

Following intravitreal administration of 2 mg per eye, a fraction of the administrated dose binds to the endogenous VEGF in the eye to form the inactive Aflibercept:VEGF complex. Once absorbed into the systemic circulation, Aflibercept presents in the plasma as the free unbound Aflibercept and predominantly as the inactive Aflibercept:VEGF complex. Aflibercept has a volume of distribution (Vd) of 6 L and a terminal elimination half-life (t1/2) of 5 to 6 days after iv administration of doses of 2 to 4 mg.kg-1 of Aflibercept. Aflibercept undergoes elimination through both target-mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis.

The full prescribing information for Eylea can be found here.

The license holder is Regeneron Pharmaceuticals, Inc. and the product website is www.eylea.com.

New Drug Approvals 2011 - Pt. XXIX (ruxolitinib phosphate) (Jakafi ™)

2011-11-18T12:23:00.001Z

ATC Code: L01XE18
Wikipedia:Ruxolitinib

On November 16th 2011, the FDA approved ruxolitinib phosphate (Tradename:Jakafi™ Research Code: INCB-018424), a JAK1/JAK2 inhibitor for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.

Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by scar (fibrous) tissue. Scarring of the bone marrow reduces its ability to blood cells, and can lead to anemia, bleeding problems, and a higher risk of infections due to reduced white blood cells. It is also associated with engorgement of organs suchs as the spleen and liver. Primary myelofibrosis may develop to secondary myelofibrosis - including leukemia and lymphoma. Myelofibrosis is associated with dysregulated Janus kinases JAK1 and JAK2, and some with a somatic mutation in JAK2 (JAK2V617F) (OMIM). JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines.

JAK1 (Uniprot:P23458) and JAK2 (Uniprot:O60674) are tyrosine protein kinases and members of the Janus kinase subfamily, where all members of the family contain two tandem protein kinase domains (PFAM:PF00069), one of which is catalytically active and one believed to be inactive. JAK1 and JAK2 are 43% identical by sequence and both have the 3D structure of their kinase domain determined (see e.g. PDBe:3EYH and PDBe:3Q32 for JAK1 and JAK2 respectively). Ruxolitinib is the first approved targeted JAK inhibitor, with several others in mid to late-stage clinical development (including CYT-387, GLPG-0634, INCB-28050, ONX-0803, NS-018, pacritinib (SB-1518), AZD-1480, BMS-911543, LS-104, XL-019, TG-101348, tofacitinib (CP-690550), VX-509, R-348, WHI-P131 and oclacitinib (PF-03394197) (veterinary applications)) - note these show a broad range of selectivity against the three known JAK subtypes.

Ruxolitinib (IUPAC: (R)-3-(4-(7H-pyrrolo[2,3 d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate; (Standard InCHI key: HFNKQEVNSGCOJV-OAHLLOKOSA-N) has a molecular weight of 404.36, an AlogP of 2.88 and complies with all components of Lipinski's rule of 5.

Ruxolitinib is administered orally as the phosphate salt as tablets and dosed according to platelet count (hence the large range of dosage forms). Each tablet contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib free base. The Tmax for Ruxolitinib is 1-2 hours post dosing, with exposure (Cmax and AUC) linear over a dose range of 5mg to 200mg. Oral absorption is in excess of 95%. The volume of distribution is 53-65 L, with plasma protein binding in excess of 97%. Ruxolitinib is predominantly metabolized by CYP3A4, with the two primary metabolites displaying weaker, but still significant pharmacological activity against their specific targets. Administration of ruxolitinib with ketoconazole, a potent CYP3A4 inhibitor, prolongs the half life of ruxolitinib from 3.7 to 6.0 hours, increases the C_max to 33% and the AUC to 91%. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole.

The license holder for Jakafi is Incyte, and the full prescribing information can be found here.

TACBAC 2012

2011-11-17T16:26:00.001Z

A quick reminder of the TACBAC 2012 conference. Previous conferences in the series have been excellent, and so check out the website for some initial conference details.

Internship at one of our industry partners

2011-11-16T14:41:00.001Z

One of our Industry Programme members, Novartis, has an opportunity for an internship (at Masters / postgraduate level) at their site in Basel in 2012 on a federation project with focus on chemical and patent related data, which would include amongst other things federation of some of the EMBL-EBI resources.

If you are interested, please mail a cv and covering mail to this address, before 30th November 2011.

Molecular Architecture of the Human ADMET System

2011-11-15T16:22:00.001Z

Here is an interesting graph, it the the frequency distribution of the functional PFAM domains for the human ADMET system - more specifically, it is the distribution of domain frequencies for the single domain containing proteins (the multidomain set is being curated now). The source data comes from the PharmADME site (the graph includes the "extended set").

So just 10 distinct functional domains cover almost 75% of the domains (there are a total of 46 domains in this set). By far the most frequent domain is, unsurprisingly, the cytochrome p450 domain (PF00067).

Annotating ChEMBL With Disease/Indication Data

2011-11-14T09:54:00.001Z

A surprisingly difficult thing to do is to perform a search of ChEMBL for potential anti-cancer compounds - an obvious place to start is by building a list of genes involved in cancer, and then pulling back all data against these genes, applying activity filters, etc. Alternatively you could think of searching for keywords like 'xenograft' in the assay descriptions, since these are likely to be linked quite strongly for anticancer indications. However, it is a big pain to do, far harder than it should be, but the good news is that we starting to think about fixing this, a little. A surprising number of gotcha's get in the way of doing this - for example a target clearly linked to cancer could be an anti-target in a cardiovascular project, etc.

The data in ChEMBL is largely centred around 'depositions from projects' in this case the project can be the assembled data in a publication, which was either part of, or an entire 'project' in the authors lab(s), or are depositions that aren't from the literature, for example the GSK malaria HTS dataset. Each of these projects had an intent - they were making compounds to cure gout, or malaria, etc. Capturing this 'intent' data is the key thing to try and do. It is often pretty simple to do just from the title of the paper, for example.

New Serotonin 5-HT1A Receptor Agonists with Neuroprotective Effect against Ischemic Cell Damage

as a title gives a pretty clear clue that the intent was to discover compounds useful for the treatment of stroke. That particular paper is here.

So how successful is the simple approach of looking for the disease area of a project from the titles of papers - it turns out it is pretty good, largely due to the frequent use of canonically constructed titles for the literature - "X for the treatment of Y" where X is a compound-related term and Y is a disease related term.

So it sounds like a simple problem, take the titles, tag them up with disease terms and away you go. However, this is where it gets complicated - there is not a good taxonomy/ontology for diseases, at least one that maps back into discovery space well. You can seem to get quite a way with a list of synonyms for various diseases, but the world needs a common public dictionary/vocabulary for disease terms. To balance this lack of a fantastic existing standard, there is the ATC classification for drugs, it is a little inconsistent in the way it mixes chemotypes, pathways and targets, but it is stable, accepted and robust - and all new approved drugs will be placed into this taxonomy, so let's see what ATC style tagging can achieve.

What we are specifically trying is to take neglected diseases (defined here as tuberculosis, helminth infections, schistosomiasis, trypanosomiasis, HIV/AIDS and malaria), and manually tag up the assays in ChEMBL with the corresponding ATC codes, at the 'depth' supported by the title - for example if malaria compounds are artemisinin-based, then it can be placed at a deeper level (P01BE) than just a malaria targeted approach (P01B). Of course, it's then possible to do cool things that group data across the span of the ATC classification.

We'll let you know how we get on!

Deadline Approaching for Current Recruitment in ChEMBL

2011-11-14T06:46:00.001Z

The deadline is approaching for two posts in the ChEMBL group - one a web developer, and the other a data integration position. The posts are three year fixed term contracts. Closing dates for applications is the 27th November 2011.

Further details should be available here

Web Developer (EBI_00145)
Data Integration (EBI_00144)

If you have any questions, please feel free to contact us.

Recommendations for a MySQL Chemical Data Cartridge?

2011-11-13T12:57:00.001Z

What options are there for a MySQL Chemical Structure Cartridge ? - the constraints are that the license needs to be Open (to commercial and non-commercial users). Post away in the comments, then everyone can see the answers.

Update: for a little background on our specific interests - we wish to build a deployable and distributable version (a package or vm) with a preconfigured and loaded current ChEMBL database, capable of performing full chemical search capability. Deployment could be as a Linux style package, or as an Amazon EC2 instance. Our internal systems here at the EBI are based on Oracle, and the MDL (or whatever the current name is :) ) Direct cartridge - this configuration is sometimes beyond the reach of many budgets, and so we are interested in exploring a 'free' but useful version of ChEMBL.

Update 2: So Postgres opens up quite a few more options....

Movember Donations from Outside the United Kingdom

2011-11-11T09:46:00.001Z

http://mobro.co/EBI

In responses to a question from one of the ChEMBL-og readers - I've just checked, and it is possible for non-UK residents to donate to the EBI Movember team - The Bioinformoustachians. Link for donations is above.

USAN Watch - November 2011

2011-11-11T04:50:00.001Z

The USANs for November 2011 have just been published.

USAN	Research Code	Structure	Drug Class	Therapeutic class	Target
bupivacaine	SKY-0402		synthetic small molecule	therapeutic	sodium channels
condoliase	SI-6603		enzyme	therapeutic
ixazomib	MLN-2238		synthetic small molecule	therapeutic	proteasome
ixazomib citrate	MLN-9708		synthetic small molecule prodrug	therapeutic	proteasome
panobinostat	LBH-589		synthetic small molecule	therapeutic	HDACs
tivantinib	ARQ-197		synthetic small molecule	therapeutic	MET
trelagliptin succinate	SYR-472, SYR-111472		synthetic small molecule	therapeutic	DPP-IV

Bupivicaine is a really old compound, with Bupivacaine Hydrochloride assigned a USAN in 1967, I guess it is on the list now as the non-salt form.

GPCR Structure: Squid Rhodopsin

2011-11-10T07:38:00.002Z

I missed this for some reason - two new higher resolution structures of squid rhodopsin. Anyway, it's been processed and will be added to the usual places later today. The reference is:

%T Crystallographic analysis of the primary photochemical reaction of squid rhodopsin.
%A Murakami M
%A Kouyama T
%J J. Mol. Biol.
%D 2011
%V 413
%P 615-627

Networks and Their Uses

2011-11-04T15:53:00.000Z

It sometimes takes me a little bit of time to understand and appreciate concepts that others pick up easily; one of these areas is around pathways and networks. The diagrams are great, and make great visual images. I have one on my office wall. It seems the more connections there are, the better - but can people understand these big messes as opposed to a simplified critical path map? There are now some great tools to explore these networks, things like cytoscape, and the annotation of these pathway diagrams is clearly valuable. One of the best books I’ve read of the broad field was the early book by Barabasi - ‘Linked’, but this is quite old now, and there has been a lot of progress.

I was at an excellent workshop this week at the NIH in Bethesda, and I was fortunate enough to participate in a specific workshop session around networks and perturbagens. This had some of the real thought-leaders of the field in, and it was great to put a face to some of the names from papers I had read. I do have a couple of things I still haven’t worked out yet, so I thought I’d try and write down what they are, and pose some questions to the ChEMBL-oggers for clarification, trigger some discussion, chat about examples, etc.

Fundamentally I feel that these networks must be most valuable when they are based on physical interactions, these must give better insight into mechanism. However, it is really common to have links between genes on the basis of transcriptional co-regulation, and given that there appears to be no standards for the display of physical compared to virtual interactions, I find working out what on earth is going on with a diagram really complex. Are there standard ways of representing the classes of interaction (physical obligate, physical transient, transcriptional, etc)?
Are there much literature connected to a domain level annotation of the networks; for example, prothrombin, the gla-domains, the kringles and the serine proteinase domain, etc, they all have different partners, and their partners usually bind at different surfaces. In terms of using the networks to think about regulation, surely the definition or annotation of the eptopes/binding sites must be essential in order to mine these networks?
How do people deal with mapping the effect of purturbagens onto these networks - the whole of pharmacology and drug discovery is built around quantitation of dose response, and there must be ways of showing the reconfiguration of networks as concentration of a perturbagen is raised?
The stability/stoichiometry of the components of these networks seems to be typically ignored - homo-oligomerisation is surely a valid class of interaction, and a lot of biology is based around concentration dependent oligomerisation events. Also people typically don’t seem to worry too much about stable complexes, versus more dynamic more highly kinetic interactions. Is this as big an issue as I think it might be?
How do researchers define the boundaries of these networks, is there an accepted convention to stop these networks growing too large - so how do people do pruning?
Is there anyway that people validate these networks, a sort of statistic that measures the statistical support for a particular topology, or fragility of the particular rendering of the network.?
Finally, probably again related to the validation of these networks and their usefulness in quantitative biology - do people routinely map available assays across the nodes, of course these could span many connected nodes, but mapping these pathways to bioassays must be a useful thing? This would clearly be a cool thing to try and do with ChEMBL.

So, I’m sure I just haven’t read the literature, so let me know - or if any of the points above are interesting research areas get in touch!

The Start of Movember - Clean Shaved and Ready To Grow!

2011-11-01T09:42:00.000Z

Sorry if these posts are a little off normal topic. But the majority of the member of the EBI's team for Movember assembled yesterday for a 'before' photo. Just look at all those baby faces, look at all those chins!

Meeting: Drug Discovery Oxford 2012 - Drug discovery: a job too complex for academia or industry alone?

2011-10-31T17:33:00.000Z

There is a great meeting being held in Oxford just after the Christmas break (specifically on the 5th and 6th January 2012), it's organised by the Structural Genomics Consortium, one of the longest existing advocates of Open Science in Drug Discovery.

Details of the meeting are here.

Meeting: 7th German Conference on Chemoinformatics

2011-10-28T09:54:00.001+01:00

A meeting that may be of interest to many of you - the GCC 2011 7th German Conference on Chemoinformatics, to be held from November 6th to 8th 2011 in Goslar, Germany.

The Bioinformoustachians!

2011-10-27T14:57:00.001+01:00

The EBI has a team entered for the annual Movember fund raising event - this is focussed on raising money for 'male cancers' - testicular and prostate. The team is called The Bioinformoustachians!, so please consider sponsoring us over the coming month. Of course, as well as raising money for a serious cause, there will be some fun along the way as well. Watch over the next few days, as the full team signs up - we're gonna raise Loadsamoney (hopefully).

For those unfamiliar with the idea - participants are clean shaved at the start and grow a moustache throughout the month gaining sponsorship for looking stylish/silly.

The team webpage on the movember website is here. Please consider donating, and help us, together, make a difference.

New Drug Approvals 2011 - Pt. XXVIII Clobazam (OnfiTM)

2011-10-27T06:03:00.002+01:00

ATC Code: N05BA09
Wikipedia: Clobazam

On October 24^th, the FDA approved Clobazam (Tradename: Onfi^TM; Research Code: RU-4723), a GABA_A receptor agonist, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged two years or older.

Lenox-Gastaut syndrome is a rare and severe form of epilepsy that is typically diagnosed in childhood and often persists into adulthood. LGS accounts for 1-4% of childhood epilepsies, and it is associated with multiple types of seizures, as well as, daily periods of frequent seizures.

Clobazam decreases the frequency of the LGS seizures by potentiating GABAergic neurotransmission, trough the binding of the GABA_A receptor at the benzodiazepine site.

GABA_A receptor is a protein complex of five subunits (mainly α2β2γ) located in the synapses of neurons. All GABA_A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter GABA, while a subset of GABA_A receptor complexes also contain a single binding site for benzodiazepines, also referred to as benzodiazepine receptors (BzR). Benzodiazepines, like clobazam, bind at the interface of the α and γ subunits on the GABA_A receptor. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedatory and anxiolytic effects.

Clobazam (IUPAC: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione; SMILES: CN1C(=O)CC(=O)N(c2ccccc2)c3cc(Cl)ccc13; PubChem: 2789; Chemspider: 2687; ChEMBLID: CHEMBL70418; Standard InChI Key: CXOXHMZGEKVPMT-UHFFFAOYSA-N) has a molecular weight of 300.7 Da, two hydrogen bond acceptors, no hydrogen bond donors, and has an ALogP of 2.74. Clobazam is a benzodiazepine derivative, a large and well established class of pharmacologically active compounds. So far, it is the only marketed 1,5-benzodiazenpine, being prefered over the 1,4-benzodiazepines already in the market: clonazepam and nitrazepam.

Clobazam is available as oral tablets of 5, 10 and 20mg, and the recommend daily dose is twice the amount of the tablets according to body weight. It has an apparent volume of distribution of 100L at steady state, and its relative bioavailability compared to an oral solution is 100%. The major metabolite of Clobazam is N-desmethylclobazam, which has about 1/5 of the activity of clobazam. Both compounds bind to human plasma proteins (80-90% and 70% respectively). The estimated mean elimination half-life (t_1/2) is approximately 36-42 hr for clobazam and 71-82 hr for the active metabolite.

Clobazam is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. In vitro metabolism studies demonstrate that clobazam and its active metabolite induce CYP3A4 activity in a concentration-dependent manner. N-desmethylclobazam is extensively metabolised by the polymorphic CYP2C19, therefore, dosage in patients who are known CYP2C19 poor metabolisers may need to be adjusted. For further drug-drug interactions please refer to the full prescribing information.

Clobazam has been granted an orphan drug designation because it is intended to treat a condition that affects fewer than 200,000 people.

The license holder for Onfi^TM is Lundbeck, and the full prescribing information can be found here.

Although clobazam has just been approved in the United States, it has been marketed outside of the US for several years under various brand names, including Frisium^® and Urbanyl^®, both licensed by Sanofi-Aventis. A full list of brand names can be found here.

New Drug Approvals 2011 - Pt. XXVII Deferiprone (FerriproxTM)

2011-10-26T18:02:00.006+01:00

ATC code V03AC02 Wikipedia Deferiprone
On October 14th, 2011 FDA announced the approval of Deferiprone (trade name: Ferriprox^TM) for the treatment of iron overload which is potentially fatal in patients with thalassemia. Deferiprone is an oral iron chelating agent, binding excess iron in the blood and thus making it available to excretion from the body. Thalassaemia is a inherited (mostly autosomal recessive) blood disease that can lead to anemia by causing the formation of abnormal hemoglobin molecules not able to properly bind and release oxygen. Thalassaemia (OMIM: 141800 (α-) / 141900 (β-)) is sub-classified according to which of the subunits of the hetero-tetrameric (2α/2β, UniProt: P69905 / P68871) hemoglobin is affected, contrary to sickle-cell anaemia (OMIM: 603903) which results exclusively from a specific mutation in the β subunit. The primary treatment of thalassaemia major, the severe form of β-thalassaemia, requires frequent blood transfusions to establish stable levels of functional hemoglobin but results in high levels of iron accumulating and impairing organ function. Thus, the secondary treatment aims on reducing the toxic iron levels by binding excess iron utilizing an iron chelating agent such as Deferoxamine (ChEMBL ID: CHEMBL556) requiring parenteral administration; Deferiprone has the desirable property of being orally available.

Deferiprone (3-hydroxy-1,2-dimethylpyridin-4(1H)-one, canonical SMILES: CN1C=CC(=O)C(=C1C)O, Standard InChI: InChI=1S/C7H9NO2/c1-5-7(10)6(9)3-4-8(5)2/h3-4,10H,1-2H3 , ChEMBL ID: CHEMBL556, CAS number: 30652-11-0, PubChem: CID 2972, ChemSpider: 2866) is a very simple synthetic small molecule with molecular weight of 139.152 Da, it has no rotatable bonds, two hydrogen bond acceptors, one hydrogen bond donor, ALogP of -0.14 and is thus fully rule-of-five compliant.

Ferriprox is dosed as 500 mg tablets and administred orally three times daily in doses of 25 mg/kg to 33 mg/kg body weight (rounded to the nearest half-tablet), resulting in a daily molar dose of ~38-50 mmol for a 70 kg individual. Common adverse reactions include chromaturia, nausea, vomiting and abdominal pain, among others. Ferriprox is not suitable for pregnant or nursing women. Ferriprox reaches a maximum concentration (C_max) of 20 mcg/mL, has an elimination half life (t_1/2) of 1.9 hours and is excreted renally. The volume of distribution is 1.6 L/kg and 1 L/kg in thalassaemia patients and healthy subjects, respectively. Peak serum concentrations are reached 2 to 4 hours after administration.

Ferriprox has been issued a boxed warning for its potential to cause agranulocytosis/neutropenia, hematological disorders characterized by abnormally low numbers of white blood cells potentially leading to serious infections and death.

Ferriprox is marketed and has been developed by Apotex.

The full prescribing information can be found here. Prior to its approval in North America, Ferriprox has been approved and available in Europe and Asia for several years - approval in North America had been delayed considerably by safety concerns brought forward by a clinical researcher formerly involved in the clinical studies.

Recruitment - Two positions in ChEMBL team now available

2011-10-25T08:59:00.001+01:00

We have two posts available in the ChEMBL group - one a web developer, and the other a data integration post. The positions are both for three years and will be EMBL staff contracts. Closing dates for applications is the 27th November 2011.

Further details should be available here (the links are quite fragile I'm afraid, so sorry if they do not keep working for long)

Web Developer (EBI_00145)
Data Integration (EBI_00144)

If you have any questions, please feel free to contact us.

PhD studentship at the Institute of Cancer Research

2011-10-24T17:13:00.000+01:00

From the lab of one of our collaborators comes the following......

Details of forthcoming PhD studentships at The Institute of Cancer Research ICR are now on-line; There are 12 studentships across a range of different disciplines including Biology, Chemistry, Informatics and Medical Physics. The deadline for applications is 1st December 2011.

There is a specific studentship of likely interest to ChEMBL-og readers - Identifying novel targets and target combinations for cancer using in-silico chemical biology, within the Computational Biology and Chemogenomics Team of the ICR.

This is a computational biology/lab biology PhD jointly between Dr. Bissan Al-Lazikani and Prof. Paul Workman. The project is an exciting multi-disciplnary project that will utilise bioinformatics and chemogenomics techniques, protein interaction network modelling as well as laboratory biology to identify novel drug intervention targets (and compounds) for use in combination therapies with best-in-class HSP90 inhibitors. The first two years of the project will be primarily computational (with an opportunity to do some basic Mass. Spec. proteomics work in the laboratory) and focus on multi-omics data mining, network modelling chemogenomic and druggability analysis. Discoveries made though the first two years will then be validated in the laboratory utilising RNA interference, cellular drug screening and other molecular and cellular biology techniques. The project benefits for a collaboration with Dr. Paul Huang and Dr. Julio Saez-Rodriguez (of the EMBL-EBI) who bring network proteomics and network modelling expertise.

Full details of the project can be found here.

The PhD is a four year project funded through the MRC studentship program. Please check eligibility criteria before applying.

Want to help shape the future of ChEMBL?

2011-10-24T12:41:00.002+01:00

We are planning to hold two half-day (fun) workshops in mid February next year (i.e. the week of February 13th 2012). Aimed at medicinal chemists and molecular modellers - the idea is to develop easy to use workflows for several key tasks that drug discoverers often want to do, and could do more efficiently with the ChEMBL data.

The workshops will be on campus here at Hinxton, and will start around 10.30am and finish around 3pm (lunch, coffee and cakes will be provided); the focus will be on....

Day 1 - Use of ChEMBL in lead optimisation
Day 2 - Use of ChEMBL for library design/compound purchase

If you are interested in helping, please mail us, and tell us what session you'd most like to attend. Space will be limited to around 8 attendees.

http://timetree.org/

2011-10-23T07:33:00.005+01:00

You know those arguments you sometimes get into with friends, the ones that are like "no way did lagomorphs diverge from rodents only 50 million years ago!" well there's a cool iPhone app (also available on Android) to help settle those debates, or simply satisfy idle curiosity on the timeline of evolution.

Link to the iTunes store is here. The original website for the data is http://timetree.org/

Why Movember is Important

2011-10-21T07:38:00.003+01:00

'Excluding skin cancer, prostate cancer is the most commonly diagnosed cancer among men in the US and the second most common cause of cancer death among men. It is estimated that about 1 in 6 men in the US will be diagnosed with prostate cancer during their lifetime and 1 in 36 will die from this disease.'

Quote from Cancer Facts & Figures 2010. American Cancer Society

Paper: canSAR

2011-10-21T06:21:00.002+01:00

One of our collaborators has just published a paper in NAR Database issue on an integrative system for Anticancer Drug Discovery - canSAR.

%J Nucleic Acids Research
%D 2011
%O doi:10.1093/nar/gkr881
%T canSAR: an integrated cancer public translational research and drug discovery resource
%A M.D. Halling-Brown
%A K.C. Bulusu
%A M. Patel 
%A J.E. Tym
%A B. Al-Lazikani

The website for canSAR is https://cansar.icr.ac.uk/

Some Downtime is Coming Up....

2011-10-19T13:59:00.002+01:00

Our Hinxton Data centre is being shutdown this coming weekend (Saturday 22nd and Sunday 23rd October 2011) for some essential maintenance. Most of the ChEMBL services will still run through this period from our London Data Centers.

The key exception to this is the Structure-based Druggability Service and Portal (www.ebi.ac.uk/chembl/drugebility).

Further details of the shutdown can be found here.

Registration Open for EMBO Chemical Biology 2012

2011-10-13T13:37:00.001+01:00

Registration is open for the (excellent) EMBO Chemical Biology 2012 meeting.

UKQSAR and ChemoInformatics Group Autumn 2011

2011-10-11T15:32:00.002+01:00

The UKQSAR and ChemoInformatics Group Autumn 2011 Meeting, jointly hosted by Accelrys and Astex, will be held on Thursday November 3rd at the Accelrys European Headquarters in Cambridge.

Details of the one day meeting can be found here. Looks a great meeting.

USAN Watch - October 2011

2011-10-10T16:27:00.002+01:00

The USANs for October 2011 have just been published.

USAN	Research Code	Structure	Drug Class	Therapeutic class	Target
blosozumab	LY-2541546		mAb	therapeutic	Sclerostin
cerlapirdine, cerlapirdine hydrochloride	SAM-531, PF-5212365		synthetic small molecule	therapeutic
dexmecamylamine, dexmecamylamine hydrochloride	TC-5214		synthetic small molecule	therapeutic	nAChR
evabotulinumtoxinA			enzyme	therapeutic
regorafenib	BAY-73-4506		synthetic small molecule	therapeutic	KIT PDGFR RAF RET
safinamide, safinamide mesylate	EMD-1195686		synthetic small molecule	therapeutic

2011-10-06T07:59:00.002+01:00

Are You Ready For Movember?

2011-10-05T16:48:00.002+01:00

We are.

http://uk.movember.com/

EMBL and Russian Foundation for Basic Research call for Proposals

2011-10-05T14:48:00.001+01:00

On 1 October 2011, EMBL and the Russian Foundation for Basic Research (RFBR) issued a call for joint projects. The 2012 call for financial support for a basic research project covers the following priority areas:

Structural biology
Genomics
Biomolecular chemistry
Cell biology/imaging
Technology development XFEL life science
High-performance computing

Biomolecular Chemistry will include Chemical Biology, Cheminformatics, Chemogenomics, QSAR, Predictive Toxicology, Virtual Screening, etc. The supported research must be carried out jointly by Russian and EMBL scientists and be of mutual interest. The call is open until 30 November 2011. If any Russian Federation scientists are interested in working with ChEMBL on an application for this funding call, please get in touch.

Conference: Bioinformatics for Anti-Cancer Drug Discovery

2011-09-29T18:19:00.002+01:00

There is a conference that we are presenting some new ChEMBL work and analysis at, and also there is a talk on CanSAR. The conference is at Bilkent University, in Ankara, Turkey. Dates are fairly soon though - 17th and 18th October 2011, but there is still time to submit an abstract - I wish more conferences were like this, in not having a big gap between the conference and any deadlines for submission.

The conference website is http://www.i-cancer.org/bioinformatics2011.

As an aside, I hadn't linked Ankara in Turkey before to the word Angora (Angora is an old name for Ankara), so this is the place responsible for the Angora goat, rabbit and cat!

Lipinski Seminar - Cancelled

2011-09-28T06:46:00.003+01:00

Unfortunately Chris has cancelled his entire UK trip next week, due to a patent case being heard in the States that he is involved with. Subsequently his seminar on campus next week is also cancelled.

Opinion: The Inventive and Creative Industries - Patents and Copyright

2011-09-28T06:13:00.001+01:00

Modern Drug Discovery is tough - too tough and expensive for many to actually stay the course.

In response to the painfully low innovation, productivity and return on investment from both private and public sectors, are a number of visionary programs and initiatives, attempting to change the dynamics, economics and participants in drug discovery - an example, in the US, is the NIH initiative to speed translational science from lab to clinic - NCATS. However, at times of pressure on research budgets, the community support and smooth progress of such actions are far from certain.

Other ways of lowering overall healthcare costs and/or incentivising innovation/investment are actively being explored. One central element is that of patent life - some argue for it to be longer (typically companies who wish to preserve their monopolies) and others argue for it to be shorter (patient groups/healthcare providers who wish to benefit from the low prices of generic medicines). In the US there are recent proposals to shorten patent coverage on drugs - this could save a lot of money (or at least can readily be explained in a way that appears to), but will it really provide the incentives for investment in new pharmaceuticals? When launched under a shorter exclusivity period the prices will naturally become higher in order to 1) recoup R&D costs or 2) provide satisfactory returns for investors (delete one of these dependent on your particular viewpoint!) over the shorter period. This 'naturally' higher price, and then the drop in prices as a drug becomes generic will appear to make it appear that drug companies are gouging consumers/patients even more!

It really is a lose-lose position for all sides, but there is a significant risk that patients (you, me and our families) with horrible diseases like Alzheimer's, stroke and cancer will pay the ultimate price, as we inadvertently kill the goose that lays the golden egg.

In very sharp contrast to the pressures to reduce the commercial protection of drugs (from 12 to 7 years in the US) are recent changes to the protection of copyright material. Commercial protection will extend from 50 to 70 years in Europe - otherwise many profitable works from The Beatles/The Who/The Rolling Stones would have entered the public domain, and the artists would potentially fall on hard times. The other odd thing about 'creative works' compared to 'inventive works' is how the families/estates of creative artists can somehow inherit these rights. There is a pretty ironic quote from Mick Jagger in the BBC news article referenced above.

"[The royalties] can extend their lives and the lives of their families who inherit their songs."

Don't get me wrong, I love creative works, I love recorded music. I have amassed a large collection of physical media that I regularly listen to. I love cheesy and serious artistes from the 1980's - they are as much part of my everyday life as statins and aspirin (and even more than Cigarettes and Alcohol); but honestly, are the efforts of scientists and engineers really worth less than those of a guitarist or lyricist (and the interests of the multinational conglomerates that employ them)? It is surprising, to me, that regulators/governments etc. are prepared to extend copyright (and other associated forms of commercial protection) to 'creative works' that have little tangible benefit to society - Lady Gaga or Imatinib?

Why is there a fundamentally different perception by both the public and governments of these two vested interest groups? Why is the lobbying of the creative industry so much more effective than that of the inventive industries? What can scientists, inventors, and entrepreneurs learn from the lobbying of performance artists? Why are there no longer any cool TV shows?

Note 1: For the non-UK residents, the picture above is of Cliff Richard, a 'mature' popular music star, at the forefront of efforts to extend copyright.

Note 2: To be clear, the views expressed above are my personal views, and do not reflect those of my employer.

Recruitment - Data Warehouse Developers for a new grant

2011-09-27T08:43:00.003+01:00

We have recently completed the legal formalities for an exciting collaborative grant involving the development of a service infrastructure for data from EU-funded research into non-animal tests for predicting chemical safety. - the grant is called DiXa. We are currently recruiting two positions for this grant (and there will be some additional posts later). These will be in the group of Ugis Sarkans at the EBI.

Further details on the positions can be found here.

Antibody Drugs in Development

2011-09-25T19:01:00.001+01:00

There are a large number of antibody drugs in development - there are about 580 in the current ChEMBL list (click here for Excel spreadsheet). I've stripped out some of the fields for clarity, but it should be pretty obvious what everything is.

So, given that we'll start loading our biological drug sets into ChEMBL shortly, is there any key data missing, as always, any feedback on errors, etc would be greatly appreciated. If anyone would like a file of all the sequences that we have, let me know.

A couple of notes on the data content

There will be some duplication - due primarily to the INNs not being released with Research Code information, whereas from clinicaltrials.gov they typical enter via a Research Code name - after a few months the entries are linked. So any further information on this set would be greatly appreciated....
The Phase number refers to the highest phase I could find the antibody drug reaching in the broad literature - it does not capture current status, and in fact a large number of these will have been abandoned by now.
There are some ambiguities (to me at least) over the USAN year, I use the date the name is published, USAN themselves appear to use a sometimes backdated date, this is probably due to inevitable gaps between assignment of the name and it's publication.

Another paper about ChEMBL

2011-09-24T07:11:00.003+01:00

A paper on ChEMBL has just been published in Nucleic Acids Review Database Issue. If NAR is new to you, it is the de facto place for publishing new (and updates to) online biological data sources.

A link to the advance access free, Open Access paper is here.

%T ChEMBL: a large-scale bioactivity database for drug discovery
%A A Gaulton
%A LJ Bellis
%A AP Bento
%A J Chambers
%A M Davies
%A A Hersey
%A Y Light 
%A S McGlinchey
%A D Michalovich
%A B Al-Lazikani 
%A JP Overington
%J Nucleic Acids Research
%D 2011 
%O doi:10.1093/nar/gkr777

A paper about ChEMBL

2011-09-23T08:36:00.001+01:00

There is a new paper on ChEMBL just published in Biochem. Soc. Trans. The paper itself is here (subscription required).

%T Collation and data-mining of literature bioactivity data for drug discovery
%A LJ Bellis
%A R Akhtar
%A B Al-Lazikani
%A F Atkinson
%A AP Bento 
%A J Chambers
%A M Davies
%A A Gaulton
%A A Hersey
%A K Ikeda
%A FA Krueger
%A Y Light
%A S McGlinchey
%A R Santos
%A B Stauch
%A JP Overington
%J Biochem. Soc. Trans
%V 39
%P 1365-1370
%D 2011

Gone Fishin'

2011-09-18T18:16:00.005+01:00

Things will be fairly quiet for the next week at ChEMBL Manor - we're off on our annual research retreat - this time to Kent. So please allow us a little more time to get back to emails, etc.

Protein Descriptors

2011-09-18T18:00:00.000+01:00

Some time ago we asked about protein descriptor services on the web - the long and short of it is that, there really wasn't anything that fit our needs, so we wrote one. Given a sequence it returns a long vector of descriptors, things like hydrophobicity, fraction of each amino acid, pI, and a whole bunch of other stuff. If there is interest, we could open this up as a web service - so return a JSON or XML object in real time (and for UniProt sequences have these precalculated). There will be some licensing issues for some of the descriptors, but I'm sure we can sort something out.

International Chemical Biology Society

2011-09-17T08:13:00.001+01:00

There is a new society, that many of the ChEMBL-og readers may be interested in - The International Chemical Biology Society (ICBS). The first meeting is being held October 11-12th 2011 in Kansas City. The program looks great.

Note: As of posting the ICBS website gives me, on my computer, a 'missing plugin' error, but other links seem to work.

USAN Watch - September 2011

2011-09-12T20:52:00.002+01:00

The September 2011 USANs have just been published.

USAN	Research Code	Structure	Drug Type	Drug Class	Target
amitifadine, amitifadine hydrochloride	EB-1010, DOV-21947		synthetic small molecule	therapeutic	SERT, NET, DAT
drisapersen, drisapersen sodium	GSK2402968A, h51AON23, PRO-051		antisense oligonucleotide	therapeutic
ganetespib	STA-9090		synthetic small molecule	therapeutic	HSP-90
niraparib	MK-4827		synthetic small molecule	therapeutic	PARP-1, PARP-2
pasireotide	SOM-230		peptide	therapeutic	SSR
prucalopride, prucalopride succinate	R-093877		synthetic small molecule	therapeutic	5HT4
samidorphan, samidorphan L-malate	RDC-0313-00, ALKS-33		natural product-derived small molecule	therapeutic	Opioid receptors
selexipag	ACT-293987, NS-304		synthetic small molecule	therapeutic	prostacyclin receptor
tanzisertib	CC-930		synthetic small molecule	therapeutic	JNK

Stem Cell Differentiation

2011-09-12T19:27:00.000+01:00

Over the summer one of our interns has entered some stem-cell differentiation into a small database - this is based on a literature search, followed by mapping the compounds to ChEMBL entries (or UniProt codes for protein factors). This was an Open Collaboration with Pfizer, who contributed the literature analysis, and also the mappings to the Cell Line Ontology. It is pretty fascinating to be able to control the path of differentiation with things that could potentially, one day, be drugs.

So, we could put this up as a microsite, have the data available for download, etc, if there is any interest?

Integration of a filtered set of PubChem Bioassay data into ChEMBL.

2011-09-07T13:54:00.005+01:00

A sub-set of the PubChem Bioassay data has been integrated into ChEMBL.

How is this sub-set defined ?

In PubChem, depositors may assign multiple result types to an assay. However, if an assay is deposited as a ‘confirmatory’ assay (defined as an assay where a range of SID concentrations have been tested, with a view to determining a measurement of potency), then one of the result types must be marked up as an ‘Active Concentration’ (AC) result type. Panel assays may contain many ‘AC’ result types, one per panel member. The AC result type is the calculated potency measurement from the data, and is typically an IC50, EC50, AC50, GI50 or Ki. In addition, the PubChem deposition process requires that each SID in an assay must be assigned a single ‘Activity Summary’, from a controlled vocabulary which includes ‘inactive’, ‘active’ and ‘inconclusive’.

Only assays containing ‘AC’ result types have been integrated into ChEMBL, and from these assays, only activity data and SIDs associated with ‘AC’ result types have been integrated. The ‘Activity Summary’ field in PubChem associated with each integrated activity is also captured and shown in the ‘Activity Comment’ field in ChEMBL. Panel assays are divided into separate assays in ChEMBL, one ChEMBL assay for each panel member.

How are structures normalized ?

An automatic ‘standardization’ of SID structures downloaded from PubChem is carried out prior to integration (using in house protocols). Standard inchis are generated from the standardized mol files, and used to normalize with existing ChEMBL structures. SIDs matching exactly on standard inchi to existing ChEMBL structures are assigned to the existing CHEMBLID (and the mol file already associated with the existing ChEMBL structure is used to represent the searchable structure for this CHEMBLID). Where no match to a standard inchi is achieved, the incoming SID is assigned to a new CHEMBLID, and the standardized mol file for the SID is used to represent the searchable structure. A very small number of SIDs (<0.1%) with standardized mol files that fail to produce valid standard inchis, or to load into a oracle symyx cartridge without errors, are each assigned a new CHEMBLID, and associated with a ‘null’ structure (ie: no mol file is associated with this new CHEMBLID).

How frequently is the integrated data updated ?

Updates are carried out every ChEMBL release cycle.

How are targets mapped ?

Mappings to ChEMBL targets for each integrated PubChem assay has been automated for the initial load. However, manual review of these mappings by expert curators may result in ongoing changes.

How do I filter my query results to exclude or include various data sources ?

Users who prefer to exclude the integrated PubChem data (or any other integrated external data set) from their ChEMBL web-interface searches can do so by clicking ‘Activity Source Filter’ next to the main ChEMBL search bar, and deselecting the sources not required in future searches. Note, however, that these deselections persist between browser sessions. Users querying ChEMBL database dumps directly using SQL, and wishing to achieve this same filtering, should inspect the ‘source’ table, and the foreign keys to this table in the ‘assays’ and ‘compound_records’ tables.

Visiting Speaker - Lipinski 4th October 2011, Wellcome Trust Genome Campus

2011-09-06T16:42:00.003+01:00

Chris Lipinski, of Rule of Five renown, is visiting the Genome Campus on Tuesday 4th October 2011 - he will give a talk entitled 'What is the Chemistry in Chemical Biology?'. The talk will be at 4pm. The presentation is open to all, and if you're from off campus, I'll need to arrange access for you (mail me to arrange this).

Please note - it's not possible to broadcast this talk over the web.

GPCR Structures: A2a Receptor with three inverse agonists

2011-09-04T08:41:00.000+01:00

The latest GPCR structure, published in Structure, details three ligand complexes, ZM-241385, a xanthine (XAC) and caffeine. In addition to the interpretation of the complex structures, the paper additionally the use of thermostabilisation as a strategy to generate crystallisable forms of GPCRs. Of more populist interest is, for the first time we can see the molecular basis of one of the most widely used stimulant drugs in action - caffeine.

Coordinates are accessible at PDBe:3pwh (ZM-241385 CHEMBL113142), 3rey (xanthine amine conjugate, XAC CHEMBL273094) and 3rfm (caffeine CHEMBL113).

%T Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine
%A A.S. Dore
%A N. Robertson
%A J.C. Errey
%A I. Ng
%A K. Hollenstein
%A B. Tehan
%A E. Hurrell
%A K. Bennett
%A M. Congreve
%A F. Magnani
%A C.G. Tate
%A M. Weir
%A F.H. Marshall
%J Structure 
%D 2011 
%O doi:10.1016/j.str.2011.06.014

Recruitment - Postdoc at the ICR in Computational Biology

2011-09-03T20:04:00.001+01:00

From the lab of one of our collaborators comes this job opportunity.

They are seeking a skilled, independent computational biologist with experience of large, multidisciplinary data analysis and programming to develop and apply novel computational techniques to support our cancer drug discovery efforts. They will take the lead in the development and dissemination of the integrative cancer research platform, canSAR.

The position will involve programming, in-silico research in identifying novel cancer therapeutic targets as well as the opportunity to mentor PhD students. The successful applicant will likely have a PhD in computational biology or related discipline, be adept in programming and large scale data analysis. Knowledge in the areas of database architecture, statistics or chemogenomics is advantageous.

Further details, including salary and contract term are available here.

Todays Found Natural Product: 3: Naringin/Bergamottin

2011-09-01T17:02:00.000+01:00

Your body is just full of carefully evolved and tried and tested systems to stop you taking bad or potentially damaging things into your body - smell receptors for the amines of rotting meat, visual receptors and a fantastic pattern-matching brain to allow you to see maggots, fungus, (blue color even in food is a usually a warning sign) etc. and taste receptors to warn of potentially toxic molecules. Drugs are highly regulated, quite rightly, and careful testing needs to be done to assess the safety of drugs.

Why, oh, why then, do we sell grapefruits without regulation and a license?

Terfenadine was a drug that was withdrawn following safety concerns, these side effects were sometimes induced by grapefruit consumption. Many, many, prescribing information sheets for drugs advise that there may be side effects and drug interactions with grapefruit - due to the prevalence of CYP3A4 mediated metabolism of the majority of current small molecule drugs. There is also an active internet (and scientific) literature in the use of grapefruit (or extracts) to exploit this CYP450 inhibition activity as a way to boost or extend plasma levels, or allow the use of lower doses of potentially life-saving drugs, and even drugs in a recreational setting. There is even a biotech established to develop drugs for this effect (but despite the wonders of Google I was unable to find it today (so maybe it is not in business any more)).

It is interesting to see grapefruit pitched as variously a 'wonder food' (health food stores, alternative therapists, agricultural organisations) or a potentially dangerous foodstuff to be consumed with care (many physicians and scientists - an example). Certainly, I always tell my mother, who loves the 'devils fruit', to tell her doctor that she frequently eats grapefruit whenever she gets a new prescription. A search of google (today, shows 3,030,000 hits for 'dangerous grapefruit' and 8,110,000 hits for 'healthy grapefruit', so a lot of opinions out there).

For the UK readers out there, the Daily Mail newspaper is renown for publishing conflicting health stories - here's what they say about grapefruit.

There are a number of compounds in grapefruit that are potent CYP inhibitors, including Naringin

and Bergamottin.

Well, the Florida Department of Citrus have provided some assurance. However, I'm still a little worried, I think I'll hold off until the 'Industrial Federation of Bergamottin and Naringin Producers' tells me it's fine ;)

The cartoon at the top was harvested from www.xkcd.com which is probably a site that is not safe for work (nsfw) - unless your work involves browsing cartoons with occasional adult humor.

RSS feed of Drug Approval Monographs

2011-08-31T14:34:00.000+01:00

An RSS feed has been set up for the ChEMBL-og NME Drug Approval Monographs.

Trade names and USANS to company and compound mapping

2011-08-31T14:08:00.004+01:00

The role of non-proprietary names (INNs, USANs etc.) and the maintenance of a synonym list for drugs under development is central in the accurate retrieval of information from the web. The USAN and INN process is well managed and documented, but it is possible to look a little bit further into the future with some simple web searches, as these examples show.

Firstly USANs under consideration - these are posted here. The therapeutic application of these can often be determined from the grammar of the name. So what compounds are they? Well a simple way to potentially look for these is with a simple whois lookup on the internet domain for INN_under_consideration.com. So using this simple approach one can speculate (reasonably) that golvatanib is Eisai's VEGFR2 and cMet inhibitor E-7050, currently in phase 2 trials. Quite a few non-proprietary domains are snaffled up by various domain registry companies, or held anonymously for their true owners - but the approach works for quite a few.

Secondly, Tradenames - well, the reference trademark site for the US is the United States Patents and Trademarks Office (USPTO). There are some excellent search tools, and one way of using these in the context of drug names is to search for the developer name, and then generating a list of potential candidates, again the field of use allows some association to be often made between a new drug. For example, searching with Pfizer as the "Owner" gives a list of trademarks including Xalkori (the tradename for the newly launched anti-cancer drug Crizotinib), and a number of alternative homonyms (these could be defensively filed, or for different territories). Of course, making a definitive assignment is difficult, and things can change, but these names could become quite useful when chained and mosaiced with other synonyms.

So, there's some simple things, it gets more interesting when you start to look at dates of filing, and so forth; but that is for another day, and a lot more analysis.

Disclaimer - the links above are fragile, they will change over time and may well have session ids, that won't work for you!

MIABE - Minimum Information about a Bioactive Entity

2011-08-31T12:04:00.004+01:00

Minimum Information Standards are an important feature in many aspects of science, and there is a rich history of the success of these in encouraging data interoperability across scientific resources and data analysis. An opinion paper has just been published in NRDD, that discusses bioactivity data. The paper itself seems to be open access (from my hotel room at least) - the link is here.

%T Minimum information about a bioactive entity (MIABE)

%J Nature Reviews Drug Discovery 
%V 10
%P 661-669
%D 2011
%A S. Orchard
%A B. Al-Lazikani
%A S. Bryant
%A D. Clark
%A E. Calder
%A I. Dix
%A O. Engkvist
%A M. Forster
%A A. Gaulton
%A M. Gilson
%A R. Glen
%A M. Grigorov
%A K. Hammond-Kosack
%A L. Harland
%A A. Hopkins
%A C. Larminie
%A N. Lynch
%A R. K. Mann
%A P. Murray-Rust
%A E. Lo Piparo
%A C. Southan
%A C. Steinbeck
%A D. Wishart
%A H. Hermjakob
%A J. Overington
%A J. Thornton
%O doi:10.1038/nrd3503

New Drug Approvals 2011 - Pt. XXVI - Icatibant (FirazyrTM)

2011-08-30T14:17:00.004+01:00

ATCC: C01EB19

Wikipedia: Icatibant

On the August 25th 2011, the FDA approved Icatibant (trade name: Firazyr^TM), a bradykinin B2 receptor (B2R) antagonist indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged 18 or older.

HAE is a rare genetic disease and is caused by low levels of C1-esterase inhibitor (C1-INH), the major endogenous inhibitor and regulator of the protease plasma kallikrein and the key regulator of the Factor XII/kallikrein cascade. One component this cascade is the production of bradykinin by plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein leads to excessive bradykinin production; bradykinin is a potent vasodilator, which s thought to be responsible for the characteristic HAE symptoms of localised swelling, inflammation and pain.

Icatibant treats the clinical symptoms of HAE attack by selective- and competitively binding, as an antagonist, to the B2 bradykinin receptor (B2R) (Uniprot: P30411; ChEMBL ID: CHEMBL3157; PFAM: PF00001), with similar affinity to bradykinin (1-10 nM for the B2R, while affinity for the B1R is 100-fold lower). Icatibant is the first in class agent against this target. The -tibant stem covers bradykinin antagonists.

B2R is a Rhodopsin-like receptor, 391 amino acid long, which belongs to the G protein-coupled receptor (GPCR) A3 family and is encoded by the BDKRB2 gene in humans. The amino acid sequence of B2R is:

>B2R 
MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQ
PPFLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFWAITISNN
FDWLFGETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLV
IWGCTLLLSSPMLVFRTMKEYSDEGHNVTACVISYPSLIWEVFTNMLLNVVGFLLPLSVI
TFCTMQIMQVLRNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGI
LSSCQDERIIDVITQIASFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEP
IQMENSMGTLRTSISVERQIHKLQDWAGSRQ

There are no known experimental structures of B2R, however there are several relevant homologous structures of other members of the rhodopsin-like GPCR family (see here for a current list).

Icatibant is the third drug approved in the US to treat HAE attacks. Previous drugs include Ecallantide (approved in December 2009 under the trade name Kalbitor), which is a potent, selective, reversible inhibitor of plasma kallikrein, and C1-INH (approved in October 2009 under the trade name Berinert), which is a freeze-dried human C1-esterase inhibitor concentrate.

Icatibant (IUPAC: (2S)-2-[[(3aS,7aS)-1-[2-[(2S)-2-[[(2S)-2-[[2-[[(4R)-1-[1-[2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid; ChEMBL ID: CHEMBL375218; PubChem: 71364; ChemSpider: 5293384) is a synthetic decapeptide that differs from bradykinin (a nonapeptide with an amino acid sequence RPPGFSPFR) at the amino acids' positions 3, 5, 7 and 8, which have been replaced by four non-natural amino acids, and also in one additional amino acid (a D-arginine) at the N-terminus of the bradykinin arginine at position 1. Thus, Icatibant amino acid sequence is D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg. These modifications prevent Icatibant from being metabolised by major bradykinin-metabolizing enzymes, which makes it more stable that bradykinin. Icatibant has a molecular weight of 1304.5 Da.

Icatibant can be self-administrated through an injection in the abdominal area, thus providing a new option for the treatment of acute HAE attacks. The recommended dose is 30 mg administrated subcutaneously. In the case of inadequate response or recurrence of symptoms, additional dose may be administrated at intervals of at least 6 hours, with no more than 3 doses administrated in any 24-hour period (recommended daily dose equivalent 69.0 umol).

Following a 30 mg subcutaneous dose, the absolute bioavailability of Icatibant is ca. 97%, with a plasma clearance of 245 mL/min, a mean elimination half-life of 1.4 hours and a volume of distribution of 29 L. Icatibant is extensively metabolised by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with <10% of the dose eliminated as unchanged drug. As would be anticipated for a peptide drug, Icatibant is not an inhibitor of major cytochrome P450 (CYP) isoenzymes and is not an inducer of CYP 1A2 and 3A4.

The full prescribing information can be found here.

Icatibant is marketed by Shire Human Genetic Therapies Inc. and the product website is www.firazyr.com (Since 2008, Icatibant has been approved for use in the European Union; the european SPC can be found here).

New Drug Approvals 2011 - Pt. XXV crizotinib (Xalkori®)

2011-08-28T15:15:00.005+01:00

ATCC: L01XE15

Wikipedia: Crizotinib

On the August 26th 2011, the FDA approved crizotinib (trade name:Xalkori® Research code: PF-02341066), an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by an approved FDA-approved test.

Non-small cell lung carcinomas (NSCLC) are cancers of the epithelial cells in the lung and describe all types of lung carcinomas other than small cell carcinomas. NSCLCs make up 88% of all lung carcinomas (see Cancer Research UK pages) and comprise genetically distinct classes of cancer, the most common are: Lung adenocarcinoma, large cell carcinoma and squamous cell carcinoma. Across the NSCLC types, some tumors harbour an ALK fusion protein. The EML4-ALK fusion gene has been shown to be affect the outcome of drug response and cells show resistance to EGFR inhibitors.

Crizotinib is an orally-dosed receptor tyrosine kinase inhibitor with significant activity against ALK (UniProt:Q9UM73, CHEMBL4247), HGFR (also known as c-Met) (Uniprot:P08581 CHEMBL3717) and RON (UniProt:Q04912, CHEMBL2689), and it is the first in class agent against any of these targets. However, ALK is the main targeted protein in these ALK-dependent, EGFR inhibitor resistant cancers. ALK is a trans-membrane receptor tyrosine kinase with the regulatory domains being extracellular and the kinase catalytic domain intracellular. The amino-acid sequence of the full wild type kinase is:


>ALK (full length wild type, kinase domain in red)
MGAIGLLWLLPLLLSTAAVGSGMGTGQRAGSPAAGPPLQPREPLSYSRLQRKSLAVDFVV
PSLFRVYARDLLLPPSSSELKAGRPEARGSLALDCAPLLRLLGPAPGVSWTAGSPAPAEA
RTLSRVLKGGSVRKLRRAKQLVLELGEEAILEGCVGPPGEAAVGLLQFNLSELFSWWIRQ
GEGRLRIRLMPEKKASEVGREGRLSAAIRASQPRLLFQIFGTGHSSLESPTNMPSPSPDY
FTWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLRNQSWSWRRIPSEEASQ
MDLLDGPGAERSKEMPRGSFLLLNTSADSKHTILSPWMRSSSEHCTLAVSVHRHLQPSGR
YIAQLLPHNEAAREILLMPTPGKHGWTVLQGRIGRPDNPFRVALEYISSGNRSLSAVDFF
ALKNCSEGTSPGSKMALQSSFTCWNGTVLQLGQACDFHQDCAQGEDESQMCRKLPVGFYC
NFEDGFCGWTQGTLSPHTPQWQVRTLKDARFQDHQDHALLLSTTDVPASESATVTSATFP
APIKSSPCELRMSWLIRGVLRGNVSLVLVENKTGKEQGRMVWHVAAYEGLSLWQWMVLPL
LDVSDRFWLQMVAWWGQGSRAIVAFDNISISLDCYLTISGEDKILQNTAPKSRNLFERNP
NKELKPGENSPRQTPIFDPTVHWLFTTCGASGPHGPTQAQCNNAYQNSNLSVEVGSEGPL
KGIQIWKVPATDTYSISGYGAAGGKGGKNTMMRSHGVSVLGIFNLEKDDMLYILVGQQGE
DACPSTNQLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGATYVFKMKDGVPVPLII
AAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWAGKSLQEGA
TGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFIS
PLGILYTPALKVMEGHGEVNIKHYLNCSHCEVDECHMDPESHKVICFCDHGTVLAEDGVS
CIVSPTPEPHLPLSLILSVVTSALVAALVLAFSGIMIVYRRKHQELQAMQMELQSPEYKL
SKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHGAFGEVYEGQVSGMPN
DPSPLQVAVKTLPEVCSEQDELDFLMEALIISKFNHQNIVRCIGVSLQSLPRFILLELMA
GGDLKSFLRETRPRPSQPSSLAMLDLLHVARDIACGCQYLEENHFIHRDIAARNCLLTCP
GPGRVAKIGDFGMARDIYRASYYRKGGCAMLPVKWMPPEAFMEGIFTSKTDTWSFGVLLW
EIFSLGYMPYPSKSNQEVLEFVTSGGRMDPPKNCPGPVYRIMTQCWQHQPEDRPNFAIIL
ERIEYCTQDPDVINTALPIEYGPLVEEEEKVPVRPKDPEGVPPLLVSQQAKREEERSPAA
PPPLPTTSSGKAAKKPTAAEISVRVPRGPAVEGGHVNMAFSQSNPPSELHKVHGSRNKPT
SLWNPTYGSWFTEKPTKKNNPIAKKEPHDRGNLGLEGSCTVPPNVATGRLPGASLLLEPS
SLTANMKEVPLFRLRHFPCGNVNYGYQQQGLPLEAATAPGAGHYEDTILKSKNSMNQPGP

The ELM4-ALK translocation protduces a chimeric protein with the N-terminal part of ELM4 and the catalytic region of ALK. This chimeria is constitutively active causing unregulated proliferation (Soda et al)

The structure of ALK in complex with crizotinib has been determined (2XP2)

ALK and other proteins inhibited by crizotinib are members of the large protein kinase family, the target of several other recently approved drugs - with the approval of crizotinib there are now 12 US approved small molecule protein kinase inhibitors (Imatinib, Gefitinib, Erlotinib, Sorafenib, Dasatinib, Sunitinib, Nilotinib, Lapatinib, Pazopanib, Vandetanib & Vemurafenib), with over an additional 300 protein kinase inhibitors that have progressed to clinical trials.

The molecular formula for crizotinib is C21H22Cl2FN5O, with a molecular weight of 450.34 Da. (IUPAC: (R)-3-[1-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine, Canonical SMILES:CC(C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N, InChI key:KTEIFNKAUNYNJU-GFCCVEGCSA-N, Chemspider:9801307, PubChem:11626560). It is fully rule of five compliant. Crizotinib has two ionizable centres with a pKa of 9.4 (for the piperidinium cation) and 5.6 (for the pyridinium cation). The experimental logD (octanol/water) at pH 7.4 is 1.65. Crizotinib is a chirally pure, synthetic small molecule drug.

Standard dosing of Crizotinib is 250mg twice daily (so a 500 mg daily dose - equivalent to 1,110 umol). The mean absolute bioavailability of Crizotinib is 43% following the administration of a single 250 mg oral dose. Crizotinib shows a median time to achieve peak concentration (Tmax) of 4 to 6 hours. Following crizotinib 250 mg twice daily dosing, steady state drug levels are reached within 15 days. The volume of distribution (Vss) of crizotinib is 1,772 L (following intravenous administration of a 50 mg dose) - so crizotinib is extensively distribution into tissues from the plasma; plasma protein binding (ppb) is 91%, and it is a substrate for P-glycoprotein (P-gp).

Crizotinib is predominantly metabolized by CYP3A4 and CYP3A5. The primary metabolic pathways in humans are oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, followed by subsequent Phase 2 conjugation of O-dealkylated metabolites. Crizotinib is an inhibitor of CYP3A. The mean apparent plasma terminal half-life of crizotinib iss 42 hours, with an apparent clearance (CL/F) of 100 L/hr following a single dose, or 60 L/hr for the 250 mg twice daily standard dosing - this is most likely due to inhibition of CYP3A4/5.

Crizotinib is marketed by Pfizer, full prescribing information can be found here.

ChEMBL-og NME Approval Monographs now on ChEMBL site

2011-08-27T11:26:00.004+01:00

We've added a cumulative list of the ChEMBL-og drug monographs to the ChEMBL web interface. As new drugs, more specifically new molecular entities (NMES)) are approved (currently in the US) we write a short, consistent monograph on each approval. Coverage is from 2009 onwards. These typically appear a few days after the approval. We also provide a set of assignments (Rule of Five, Chiral, Black Box Warnings, etc.) for each drug. Some of these assignments are subjective, for example assigning a drug as natural product-derived is sometimes challenging.

We try to keep these current, so there will be inconsistency between the views through the ChEMBL interface and on this page, but this is currently inevitable in our versioned release of ChEMBL.

Any feedback on the view, data, etc. would be gratefully received.

ChEMBL Release Scheduling

2011-08-26T15:27:00.002+01:00

We are currently reviewing our internal release process for ChEMBL, and have a question. When we do a release, there are sometimes changes to the schema (we generally detail these in the release notes of previous releases) and also changes to deprecated items (targets or compounds that have changed or disappeared). We now also have a series of sites that use the ChEMBL data to provide new services, and these will invariably break (often both in and outbound links) as loading and processing of the ChEMBL data happens in these other systems.

One of the ideas we are considering is to have a 'pre-release' of the forthcoming release to interested parties during our normal one or two week long testing period. This could allow a smoother release schedule, and also help us with support issues after releases, but I'm sure have some further problems for us. So, if you run a resource, using ChEMBL and would like to discuss this with us, or if you have other views, we'd be happy to hear (mail link).

PhD studentship Available for Oct 2012 Intake

2011-08-26T11:25:00.002+01:00

We will be recruiting a PhD student to start in October 2012. Details of the application process can be found at www.embl.org/phdprogramme. The deadlines are important - you will need to register by December 1st 2011, with a final deadline of 12th December 2011.

There is a lot of exciting research in chemical biology at EMBL, and ideas for potential PhD projects within the chembl group include:

Design of biopharmaceuticals using rule-based approaches.
Drug design strategies to improve drug safety.
Multi-scale indexing, visualisation and navigation of chemical structures.
Drug attrition analysed using systems biology and simulation approaches.

However, we would be really keen to discuss your interests if you do apply. Contact us if you wish to discuss anything.

ChEMBL Identifiers

2011-08-22T12:07:00.000+01:00

A few notes about the use and format of identifiers in ChEMBL:

Each of the major entity types within ChEMBL (documents, assays, compounds and targets) are assigned unique ChEMBL identifiers, which take the form of a ‘CHEMBL’ prefix followed immediately by an integer (e.g., CHEMBL25 is the compound aspirin, CHEMBL210 is the human beta-2 adrenergic receptor "target"). There is no distinction between the format of the identifier for different types of entities, but a given ChEMBL identifier will only ever be assigned to a single entity (i.e., CHEMBL25 will only ever be used for the compound aspirin and never for an assay, document or target). A lookup table is provided in the database, to resolve which identifiers correspond to which entity types.

ChEMBL identifiers are stable with respect to the entities they represent. For compounds (with known/defined structures), ChEMBL identifiers represent distinct compound structures, as defined by the standard InChI, e.g., CHEMBL25 represents: InChI=1S/C9H8O4/c1-6(10)13-8-5-3-2-4-7(8)9(11)12/h2-5H,1H3,(H,11,12). Therefore, two compounds reported in different papers but having the same standard InChI will be assigned the same ChEMBL ID.

These ChEMBL IDs will never be reassigned to a structure with a different standard InChI. However, since compounds may be reported or drawn incorrectly in the literature, it is sometimes necessary to alter the compound ChEMBL ID (structure) to which a particular bioactivity measurement links. In this case, the old (incorrect) ChEMBL identifier may be 'downgraded' in the database if no other data link to it. Downgraded compounds are not currently displayed on the live interface, but are retained in the database and the ChEMBL ID lookup table, and could be re-instated in future (with the same ChEMBL ID) if new data become available for them.

External identifiers for ChEMBL entities are also recorded in the database, where possible. For example, in addition to ChEMBL IDs and InChI/InChIKeys, all small molecule compounds with defined structures are assigned ChEBI identifiers. Where data are taken from other resources, the original identifiers are also retained (e.g., SIDs and AIDs for PubChem substances and assays, HET codes for PDBe ligands). PubMed identifiers or Digital Object Identifiers (DOIs) are stored for documents, and protein targets are represented by primary accessions from the UniProt database.

New Drug Approvals 2011 - Pt. XXIV Vemurafenib (Zelboraf TM)

2011-08-22T08:45:00.005+01:00

ATC code: L01XE15

Wikipedia: Vemurafenib

On the August 17th 2011, the FDA approved Vemurafenib (trade name:Zelboraf ^TM Research code: PLX-4032, RG-7204 and RO-5185426), a BRAF kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the mutant BRAF^V600E.

Melanoma is a malignant tumor of melanocytes (skin cells that produce melanin) and is an aggressive disease responsible for an estimated 50,000 deaths worldwide. Over 50% of patients with advanced melanoma carry an activating mutation in the Serine/Theronine protein kinase: BRAF (V600E).
The MAPK signal transduction pathway is an important and frequently mutated pathway in cancer. A wide variety of growth factors signal through this pathway, via RAS and RAF proteins to cause cell proliferation. The activating mutation in BRAF causes activation of this pathway downstream of BRAF regardless of the presence of growth factor (the signalling pathway is 'dysregulated'). The protein of Vemurafenib is this mutant enzyme BRAF^V600E (Uniprot:P15056(wt)), although it shows activity in vitro against other protein kinases including such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar affinities.

One side effect observed in nearly a quarter of patients is the paradoxical growth of cutaneous squamous cell carcinomas (cuSCC), a different, and less aggressive type of skin cancer. Intriguingly, this appears to be cause by activating the same pathway in normal cells of the same patient that carry a RAS mutation.

>BRAF
MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADPAIPEEVWNIKQMIKLTQEHIEALLDK
FGGEHNPPSIYLEAYEEYTSKLDALQQREQQLLESLGNGTDFSVSSSASMDTVTSSSSSSLSVLPSS
LSVFQNPTDVARSNPKSPQKPIVRVFLPNKQRTVVPARCGVTVRDSLKKALMMRGLIPECCAVYRIQ
DGEKKPIGWDTDISWLTGEELHVEVLENVPLTTHNFVRKTFFTLAFCDFCRKLLFQGFRCQTCGYKF
HQRCSTEVPLMCVNYDQLDLLFVSKFFEHHPIPQEEASLAETALTSGSSPSAPASDSIGPQILTSPS
PSKSIPIPQPFRPADEDHRNQFGQRDRSSSAPNVHINTIEPVNIDDLIRDQGFRGDGGSTTGLSATP
PASLPGSLTNVKALQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFG
TVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSS
LYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLAT[V/E]
KSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIF
MVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPKIHRSASEPSLN
RAGFQTEDFSLYACASPKTPIQAGGYGAFPVH

The structure of Vemurafenib complexed to BRAF is known (PDBe:3og7).

Vemurafenib

Vemurafenib (Molecular formula: C23H18ClF2N3O3S; IUPAC: N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide; Canonical smiles: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(cc23)c4ccc(Cl)cc4)c1F ; standard InChI: 1S/C23H18ClF2N3O3S/c1-2-9-33(31,32)29-19-8-7-18(25)20(21(19)26)22(30)17-12-28-23-16(17)10-14(11-27-23)13-3-5-15(24)6-4-13/h3-8,10-12,29H,2,9H2,1H3,(H,27,28) CHEMBL1229517, Chemspider:24747352, PubChem:CID 42611257). Vemurafenib is a synthetic small molecule drug, with no chiral centres, it has a molecular weight of 489.9 MWt and is fully rule of Five compliant.

Vemurafenib is orally administered as tablets, each tablet contains 240 mg of active compound - dosing is 960 mg twice daily (equivalent to 3920 umol). The bioavailability of vemurafenib has not been determined. Following oral administration of vemurafenib at 960 mg twice daily for 15 days to patients with metastatic melanoma, the median Tmax was approximately 3 hours. Vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and is a CYP3A4 inducer, it is highly bound to serum albumin and alpha-1 acid glycoprotein (> 99% ppb). In treated patient populations the apparent volume of distribution is 106 L, the clearance is 31 L/day and the median half life is 57 hours. It is largely excreted in feces (94% of dose).

Vemurafenib is also notable in being arguably the first drug discovered and optimised using fragment soaking methods for initial lead discovery. Vemurafenib was discovered in the labs of Plexxikon.

Full US Prescribing information is here

Zelboraf is marketed by Hoffmann-La Roche Inc.

New Drug Approvals 2011 - Pt. XXV Brentuximab vedotin (AdcetrisTM)

2011-08-21T14:34:00.003+01:00

ATC code:L01XC12
On 19th August 2011, the FDA approved Brentuximab vedotin (trade name Adcetris^TM, ATC code:L01XC12, research code:SGN-35, aAC10-vcMMAE), a antibody drug conjugate (ADC) targeting CD-30, indicated for the treatment of patients with Hodgkin's lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates (1.1); and the treatment of patients with systemic anapaestic large-cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen.

Hodgkin's lymphoma is a cancer of cells derived from white blood cells called lymphocytes. In Hodgkin's lymphoma, the disease spreads from one lymph node group to another, and then leads to more systemic effects. Hodgkin's lymphoma can be treated with radiation therapy, chemotherapy or autologous hematopoietic stem cell transplantation. The occurrence of the disease shows two age peaks: the first in young adulthood (age 15–35) and the second in those over 55 years old

Brentuximab vedotin's molecular (for the antibody component of the ADC, Brentuximab) target is CD30 (Uniprot: P28908; canSAR ; PFAM: PF00020), which is expressed on activated T- and B-cells, and also is an established tumour marker. Endogenous CD30 ligands include TRAF1, TRAF2, TRAF3 and TRAF5. CD30 is a transmembrane protein, 577 amino acid long, containing three related copies of the TNFR_c6 domain (PFAM:PF00020). The structure of TRAF2 complexed to part of CD30 is known (see PDBe:1d01)

The antibody component Brentuximab binds to CD30 expressing cells, the the complex is then internalised, and the cytotoxic agent Monomethyl auristatin E (MMAE) which blocks cell division by preventing tubulin polymerisation. Auristatin is a marine natural product peptide derivative. There are approximately 4 copies of MMAE coupled to each antibody, and MMAE is linked through a protease activatable linker. The total molecular weight of Brentuximab vedotin is ca. 153 kDa. Brentuximab can therefore be considered to have two targets (CD30 and tubulin), and also to be a prodrug.

Brentuxumab vedotin is the second US approved antibody drug conjugate - the first being gemtuzumab ozagamicin (Mylotarg) which was approved in 2001, but subsequently withdrawn from the market. A significant number of ADCs are currently in clinical development.

Brentuximab is a human antibody. The antibody portion of Brentuximab vedotin has the sequence of two copies of:

>Brentuximab vedotin - heavy chain
QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKY
NEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSAAST 
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV 
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY 
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG 
NVFSCSVMHEALHNHYTQKSLSLSPG
>Brentuximab vedotin - light chain
DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLES 
GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIKRTVAAPSVF 
IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS 
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

The linker-MMAE has the following structure:

Brentuximab is administered intravenously, and the recommended dose is 1.8 mg/kg administered over 30 minutes every 3 weeks for a maximum of sixteen cycles doses. The terminal half-life (t_1/2) is 4 to 6 days.

The full US prescribing information for Brentuximab vedotin can be found here. Adcetris™ is a product of Seattle Genetics

USAN Watch - August 2011

2011-08-11T17:57:00.005+01:00

The August 2011 USANs have just been published.

USAN	Research Code	Structure	Drug Type	Drug Class	Target
flanvotumab	IMC-20DS7		monoclocal antibody	therapeutic	gp75
glycerol phenylbutyrate	HPN-100		synthetic small molecule prodrug	therapeutic	n/a
orteronel	TAK-700		synthetic small molecule drug	therapeutic	steroid 17-alpha hydroxylase/17,20 lyase
plazomicin	ACHN-490		natural product-derived drug	therapeutic	30S ribosome
radavirsen	AVI-7100		oligonucleotide derived	therapeutic	Influenza virus
rasagiline	TV-1030		synthetic small molecule	therapeutic	MAO-B
romosozumab	AMG-785		monoclonal antibody	therapeutic	sclerostin
setrobuvir	ANA-598		synthetic small molecule	therapeutic	HCV polymerase
sutezolid	PNU-100480, PF-02341272		synthetic small molecule	therapeutic	50S ribosome
tozadenant	SYN-115, RO-4494351		synthetic small molecule	therapeutic	A2a receptor
trelagliptin	SYR-472		synthetic small molecule	therapeutic	DPP-4
trebananib	AMG-386		antibody derived	therapeutic	angiopoietin1/2
umeclidinium, umeclidinium bromide	GSK-573719,		synthetic small molecule	therapeutic	muscarinic receptors