CEP-32496 (free base)

B-Raf is a MAP kinase kinase kinase, which functions downstream of Ras family GTPases to activate MEK1/2 and ERK1/2 signaling. Mutations of B-Raf, particularly at Val⁶⁰⁰, are common in melanomas and melanocytic nevi. CEP-32496 is a potent inhibitor of B-Raf^V600E (K_d = 14 nM in an in vitro binding assay). It blocks B-Raf^V600E-dependent phosphorylation of MEK in human melanoma A375 and colorectal cancer COLO 205 cells (IC₅₀s = 78 and 60 nM, respectively). CEP-32496 binds kinases other than B-Raf but displays selective cytotoxicity for cells expressing B-Raf^V600E. It displays good oral bioavailability in rats, dogs, and monkeys and has single oral dose pharmacodynamics inhibition of both pMEK and pERK in B-Raf^V600E colon carcinoma xenografts in nude mice.

CEP 32496 is an orally active BRAFV600E inhibitor with selective cellular and in vivo antitumor activity.