2. Academic Validation
  3. 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

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.
Martin W Rowbottom 1,  Raffaella Faraoni,  Qi Chao,  Brian T Campbell,  Andiliy G Lai,  Eduardo Setti,  Maiko Ezawa,  Kelly G Sprankle,  Sunny Abraham,  Lan Tran,  Brian Struss,  Michael Gibney,  Robert C Armstrong,  Ruwanthi N Gunawardane,  Ronald R Nepomuceno,  Ianina Valenta,  Helen Hua,  Michael F Gardner,  Merryl D Cramer,  Dana Gitnick,  Darren E Insko,  Julius L Apuy,  Susan Jones-Bolin,  Arup K Ghose,  Torsten Herbertz,  Mark A Ator,  Bruce D Dorsey,  Bruce Ruggeri,  Michael Williams,  Shripad Bhagwat,  Joyce James,  Mark W Holladay
Affiliations

Affiliation

  • 1 Ambit Biosciences, 4215 Sorrento Valley Boulevard, San Diego, California 92121, United States. mrowbottom@ambitbio.com
PMID: 22168626 DOI: 10.1021/jm2009925
Abstract

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. Expression of mutant BRaf(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRaf(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRaf(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRaf(V600E) versus those containing wild-type BRaf. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRaf(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.

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