The ChEMBL-og

ATC code : L01XE13 Wikipedia : Afatinib On July 12th 2013 the FDA approved Gilotrif TM (USAN afatinib) for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) carrying EGFR exon 19 deletions or exon 21 (L858R) mutation. It is a covalent, irreversible inhibitor of EGFR, ERBB2 and ERBB3. Non small cell lung cancer (NCLS) ( CRUK NCLS ; PDQ NCLS ) accounts for 78% of lung cancer incidences in the UK and is typically resistant to chemotherapy. In clinical studies, afatinib increased the mean Progression Free Survival to 11.1 months from 6.9 months (compared to standard of care Pemetrexed/Cisplatin). Furthermore, response to treatment was observed in tumors harboring several EGFR mutant species although the duration of response varied from 6.9 months to 16.5 months depending on the mutation . Afatinib covalently binds to the kinase domains of EGFR (ErbB1, Uniprot: P00533 ; canSAR: EGFR ”), HER2 (ErbB2, Uniprot: P04626 ;...

ATC code: L01XE15 Wikipedia: Trametinib ChEMBL2103875 On May 29th 2013, the FDA approved trametinib (Mekinist®) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, and who have not received prior BRAF inhibitor treatment. Trametinib inhibits mutant BRAF signalling through the inhibition of a downstream kinase, MEK. In clinical trials trametinib improved the progression-free survival (PFS) from 1.5 months on standard of care chemotherapy to 4.8 months on trametinib. Trametinib is the first approved targeted MEK inhibitor. It inhibits the kinase catalytic activity of its targets, mitogen-activated extracellular signal regulated kinase 1 and 2 ( MAP2K1 AKA MEK1, Uniprot: Q02750 ) and MAP2K2 AKA MEK2, Uniprot: P36507 ). The sequences of the targets are here: >sp|Q02750|MP2K1_HUMAN Dual specificity mitogen-activated protein kinase kinase 1 OS=Homo sapiens GN=MAP2K1 PE=1 SV=2 MPKKKPTPIQLNPAPDGSAVNGTSSAETNLEALQKKLEE...

ATC code: L01XE15 Wikipedia: Dabrafenib On May 29th 2013 the FDA approved dabrafenib mesylate (trade name: Tafinlar®, research codes GSK-2118436A and GSK-2118436B) for the treatment of patients with unresectable metastatic melanoma harbouring the BRAF V600E mutation. In clinical trials, dabrafenib showed improved progression-free survival (PFS) over the comparator dacarbazine (median PFS 5.1 months for dabrafenib compared to 2.7 months for dacarbazine). Moreover, in a multicentre open-label Phase II trial dabrafenib showed effectiveness on brain metastases of melanoma regardless of whether the patients had been previously treated. As with the previously approved BRAF inhibitor, vemurafenib, the major side effect of dabrafenib is the emergence of malignant cutaneous squamous cell carcinomas and keratoacanthomas. The main molecular target for dabrafenib is the human mutant serine/threonine kinase, BRAF (Uniprot for wild type protein: P15056 ). ...

The Protein Kinase Inhibitor Set (PKIS) made available by GSK was recently mentioned on  In the Pipeline .  In collaboration with GSK, we are making the data being generated on these compounds available via  the ChEMBL database.  We are also creating a portal for the compound set, where the structures can be browsed and downloaded, direct links to the data are provided and useful information can be posted. A preliminary version is available  here : feedback would be appreciated. The data generated on the PKIS set and deposited in ChEMBL may be downloaded in CSV format here  (note that the Luciferase dataset described in the recent PLoS paper will be in the next release of ChEMBL). Alternatively, to view the data in the ChEMBL web interface, follow these steps: On the home page, enter 'GSK_PKIS' in the search box and click on the 'Assays' button... On the 'Please select...' menu on the right, choose 'Display Bioactivities'... ...

We've just processed and integrated a new full matrix  kinase inhibition dataset, kindly provided by EMD Millipore . As described in this  recent paper, it covers  234 human wildtype kinases and kinase complexes, as well as 158 'standard' kinase inhibitors tested at two concentrations, leading to more than 73,000 data points. Analysis of the data could provide new insights to kinase selectivity/promiscuity/polypharmacology (depends on how you look at it) and their relationship with chemical structure. The dataset will be available with ChEMBL_16 next month.  PS:  The image above shows the activity profile of four kinase inhibitors across the human kinome families from the Millipore data. It was produced with circos  by Rita.  George

One of our Industry Programme members passed on a listing for some positions they are looking to fill at the new center in Heidelberg - BioMed X. It looks like it may be of interest to many of the ChEMBL-og readers, so I thought I would post it here.... They are looking for a Computational Chemistry/Drug Design group leader for a project "Development of a design software of SELECTIVE kinase inhibitors". The BioMed X Innovation Center in Heidelberg, Germany, constitutes a new class of incubator at the interface between academia and industry where top life science talents from all over the world are jointly working on biomedical innovation outside the pharma box. Young talents from leading academic institutions world-wide are selected in annual assessment centers based on their scientific expertise, creative energy, and passion for product-oriented pre-clinical research & development. Interdisciplinary project teams are collaborating in an open-innovation lab facility in...

ATC code: not yet assigned Wikipedia: Cabozantinib On November 29th, the FDA approved  Cometriq TM (cabozantinib, research code XL-184) for the treatment of patients with progressive, metastatic, medullary thyroid cancer (MTC). MTC is a rare type of thyroid cancer accounting for 5-10% of all diagnosed thyroid cancers ( CRUK ). A quarter of MTC cases are familial and are caused by a mutation in the RET gene. Clinical studies showed that cabozantinib increases progression-free survival time to 11.2 months in comparison with 4 months for placebo. Cabozantinib (research codes: XL-184, BMS-907351; IUPAC:  Cabozantinib ( S )-malate is described chemically as N -(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)- N’ -(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide, Standard InChI:  ONIQOQHATWINJY-UHFFFAOYSA-N) is dosed as the (S)-malate salt. The parent molecule, cabozantinib, has a molecular weight of 501.5 and a ACD/LogP of 3.08. The effective half-life is ~55 ho...

On November 6, the  FDA approved   T ofacitinib  citrate (Trade Name:  XELJANZ® ; Research code: CP-690550, ChEMBL :  CHEMBL221959 , PubChem:  CID9926791 , DrugBank:  DB08183 , ChemSpider:  8102425 )  to treat moderately to severely active  Rheumatoid Arthritis  (RA). It is orally administered and may be used as monotherapy agent or in combination of non-biologic  DMARDs . About 1% of the world-wide population is affected by  rheumatoid arthritis .  RA affects predominantly women ( three times more susceptible than men ) and is more frequent between ages 40 and 50, but people of any age can be affected . Other approved drugs in this commercially competitive sector include  Adalimumab (Trade Name:   Humira , ChEMBL: CHEMBL1201580 , DrugBank: DB00051 ) , Etanercept (Trade Name:  Enbrel ,  ChEMBL: CHEMBL1201572 , DrugBank: DB00005 ) , Infliximab (Trade Name:  Remic...

ATC code: L01XE21 Wikipedia: Regorafenib On September 27th 2012 the FDA approved Stivarga (Regorafenib) for the treatment of metastatic colorectal cancer who have previously received chemotherapy, anti-EGFR or anti-VEGF therapy. Colorectal or bowl cancer is one of the most common cancers in the western world, is the third most common cancer in the United States and the second most common cause of cancer deaths in the United Kingdom (according to CRUK ). While Five-year survival rates of the primary cancer have been improving due to the availability of targeted therapy, they only extend to about 50%, however, the metastatic disease has poor prognosis. In clinical trials Regorafenib showed statistically significant improvement in survival of patients with metastatic disease as compared to the best standard care alone, with the median survival being extended from 5 to 6.4 months. Regorafenib (research code: BAY-73-4506; chembl id : CHEMBL1946170 is a monohydrate ...

On September 4th, the FDA approved  bosutinib (marketed as Bosulif) for the treatment of patients with previously treated Philadelphia Chromosome-Positive (Ph+)  Chronic Myelogenous Leukemia (CML - cancer of the white blood cells). Chronic myelogenous leukemia is one of the four most common types of leukemia and is often associated with treatment with imatinib ( CHEMBL941 ) as an initial therapy. However, approximately one-third of patients do not achieve an optimal response with this standard treatment. In such cases, second generation Tyrosine Kinase Inhibitors are required, but only half of the treated patients show acceptable outcomes. The patients with poor responses to either of these treatments have now the possibility to receive bosutinib ( CHEMBL288441 ) as alternative therapy. As suggested by the '-tinib' prefix (USAN stem), bosutinib is a protein kinase inhibitor ( ATC:L01XE14 ). The molecule has a calculated logP of 3.88 and relative m...

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 extr...

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 signalin...

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. C rizotinib is an orally-dosed recep...

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...

Not Moon Safari but Kinase SARfari ! There are a lot of changes to the interface and integration of data, and also oodles more data (104% more) contained in the latest release. These include: Unified SARREGNOs to CHEMBL IDs (also Assay & Doc ids). Updated assays, activities and compounds from ChEMBL_10. Added 30 non-human kinase domains. Calculated site similarity distances and neighbourhood density (ND) scores between all kinase domains. Added Drug Icons into the interface. Added links to ChEMBL Target/Doc/Assay Report Cards. Renamed old sources (drugstore & candistore). Contents: Kinase domains: 989, Kinase bioactivity datapoints: 435,873, Kinase compounds: 51,090. For the time being, the new version can be found on our dev site at http://wwwdev.ebi.ac.uk/chembl/sarfari/kinasesarfari . As always, we would appreciate any bug reports, feedback, etc .

ATC code: L01XE12 On the 6th April 2011, the FDA approved Vandetanib (trade name: Zactima TM , ATC code: L01XE12, NDA 022405), a multi-kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. ( medullary thyroid cancer ; CRUK Thyroid cancer ; ICD C73 ) Medullary thyroid cancer is a rare form of Thyroid cancer, but is associated with poorer prognosis. While the primary tumor can be successfully removed using surgery and radiotherapy, and thus can have a high 5 and 10 year survival rate (>90%), the metastatic disease remains challenging and is has a low 40% survival rate. Medullary thyroid cancer can be a sporadic or hereditary disease, and has complex underlying genetic causes. Approximately 25% of cases are associated with the RET (REarranged during Transfection) proto-oncogene. RET mutations cause Multiple Endocrine Neoplasia type 2 (MEN 2) which increases the r...

A new data load for kinase SARfari screening data has just been completed. There is a significant growth in both the number of inhibitors (28,016 vs. 17,028), and the number of assay data-points (147,478 vs. 68,861). It is available here Remember it is a test version only, and if you do find any problems, please mail them... Finally, there is a funny story behind the picture, which will emerge over the next few blog posts.

Another drug onto the market this month is Pazopanib, marketed as Votrient, which was approved on October 19th. Pazopanib Hydrochloride (previously known as GW-786034-B) is the sixth drug to be approved for kidney cancer, after Sorafenib (trade name Nexavar), Sunitinib (trade name Sutent), Temsirolimus (trade name Torisel), Everolimus (trade name Afinitor) and Bevacizumab (trade name Avastin). Sorafenib and Sunitinib are both orally dosed small molecule inhibitors of tyrosine protein kinases, which interfere with tumor growth by inhibiting angiogenesis as well as tumor cell proliferation; Temsirolimus and Everolimus are specific inhibitors of mTOR ( mammalian target of rapamycin ), a serine-threonine kinase, which interfere with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells; Bevacizumab is a monoclonal antibody that recognizes and blocks VEGF, which is a chemical signal that stimulates angiogenesis. Pazopanib is a small-molecule dru...