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)
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).
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.