ChEMBL Resources

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ECBD

Tuesday, 31 January 2012

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





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

Sunday, 29 January 2012

Japanese Drug Approvals


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 ;)

Friday, 27 January 2012

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




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.

Thursday, 26 January 2012

Paper: Quantifying the Chemical Beauty of Drugs

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


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!

Monday, 23 January 2012

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




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.

Thursday, 19 January 2012

Course - Resources for Computational Drug Discovery


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 ;)

Tuesday, 17 January 2012

EBI Open Day - 1st March 2012



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.

Friday, 13 January 2012

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


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

Friday, 6 January 2012

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


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.