CEP-32496: A Novel Orally Active BRAFV600E Inhibitor with Selective Cellular and In Vivo Antitumor Activity

Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60-70% of melanomas, 23-83% of papillary thyroid carcinomas, 4-16% colorectal cancers, and a lesser extent in serous ovarian and non-small-cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAFV600E (Kd BRAFV600E = 14 nM) and in a MEK phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC50 = 78 and 60 nM). In vitro, CEP-32496 has multi-kinase binding activity at other cancer targets of interest; however exhibits selective cellular cytotoxicity for BRAFV600E versus wildtype. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10 to 55 mg/kg) of both pMEK and pERK in BRAFV600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30 to 100 mg/kg BID) against BRAFV600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (Phase 1), sorafenib, (approved), and vemurafenib (PLX4032/RG7204), (approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side-effect profile currently in clinical development.

http://mct.aacrjournals.org/content/early/2012/02/07/1535-7163.MCT-11-0645.abstract

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