The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation and survival. Cellular expression of mutant BRAFV600E results in the constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Approximately 7% of all known human cancers express BRAFV600E, being most frequently associated with melanoma, colon, and papillary thyroid carcinomas. In the clinic, the administration of orally available BRAFV600E inhibitors has shown excellent utility in the treatment of mutant BRAF-driven carcinomas. This presentation will describe our own medicinal chemistry efforts toward the identification of orally efficacious inhibitors of BRAFV600E. An optimization campaign around an initial 5-tert-butyl-isoxazol-3-yl urea containing quinazoline lead will be described. In particular, we describe the targeted replacement of the metabolically sensitive tert-butyl moiety with a variety of bioisosteric alkyl fluoride motifs, an effort which led to the identification of a 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl urea-containing quinazoline derivative (CEP-32496). CEP-32496 exhibits high cellular potency against the BRAFV600E-dependent A375 and Colo-205 cell lines, and excellent oral exposure in multiple preclinical species. In addition, CEP-32496 proved selective for the RAF kinase members of the MAPK signaling cascade and exhibits selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. CEP-32496 also demonstrates significant oral efficacy in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model when dosed at 30 and 100 mg/kg BID. These observations coupled with excellent drug-like properties led to the selection of CEP-32496 as a clinical candidate.

Discovery of CEP-32496, a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF)<sup> </sup>V600E

243rd National Meeting (2012)

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Discovery of CEP-32496, a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E

Discovery of CEP-32496, a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF)V600E