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

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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
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