Skip to main content

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

Image
By Bissan Al-Lazikani




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
There are many VEGF inhibitors in development, and several launched drugs also have activity against  VEGFR (including Vandetanib, Sorafenib, Pazopanib and the broad spectrum inhibitor Sunitinib).
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 (T1/2varies 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
Labels:

Comments

Post a Comment

Popular posts from this blog

Improvements in SureChEMBL's chemistry search and adoption of RDKit

By Eloy
    Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by
Post a Comment
Read more

Improved querying for SureChEMBL

By
    Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never
Post a Comment
Read more

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

By
In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen
Post a Comment
Read more

ChEMBL 34 is out!

By
We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.
Post a Comment
Read more

A python client for accessing ChEMBL web services

By
Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d
1 comment
Read more