Background:

CEP-32496 is a?highly potent and orally efficacious V600E mutant BRAF, WT BRAF and c-Raf inhibitor with Kd values of 14 nM, 36 nM and 39 nM, respectively.

In addition to BRAFV600E, CEP-32496 has exhibited high binding affinity for both wild-type BRAF and related CRAF, as well as certain receptor tyrosine kinases of known therapeutic utility, such as Abl-1, c-Kit, Ret, PDGFR-β, and VEGFR-2. However,?CEP-32496?proved selective for the RAF members of the MAPK signal transduction pathway, as no significant affinity was observed for other key kinases of the MAPK pathway, including MEK-1, MEK-2, ERK-1, and ERK-2. This suggests that the observed cellular activity was driven primarily through inhibition of BRAFV600E, which is further supported by the observation that CEP-32496?exhibited selective cytotoxicity for tumor cell lines expressing mutant BRAF versus those expressing wild-type BRAF [1].

Oral administration of?CEP-32496?to Colo-205 tumor xenograft-bearing mice resulted in significant inhibition of pMEK in tumor cell lysates [1].

参考文献:
[1] Rowbottom MW1,?Faraoni R,?Chao Q,?Campbell BT,?Lai AG,?Setti E,?Ezawa M,?Sprankle KG,?Abraham S,?Tran L,?Struss B,?Gibney M,?Armstrong RC,Gunawardane RN,?Nepomuceno RR,?Valenta I,?Hua H,?Gardner MF,?Cramer MD,?Gitnick D,?Insko DE,?Apuy JL,?Jones-Bolin S,?Ghose AK,?Herbertz T,?Ator MA,Dorsey BD,?Ruggeri B,?Williams M,?Bhagwat S,?James J,?Holladay MW. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2 -methylpropan- 2-yl) isoxazol-3-yl) urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J Med Chem.?2012 Feb 9;55(3):1082-105. doi: 10.1021/jm2009925. Epub 2012 Jan 23.