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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.

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.
AuthorsMartin W Rowbottom, 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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 55 Issue 3 Pg. 1082-105 (Feb 09 2012) ISSN: 1520-4804 [Electronic] United States
PMID22168626 (Publication Type: Journal Article)
Chemical References
  • Isoxazoles
  • Phenylurea Compounds
  • Quinazolines
  • agerafenib
  • Proto-Oncogene Proteins B-raf
Topics
  • Administration, Oral
  • Animals
  • Binding, Competitive
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dogs
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Isoxazoles (chemical synthesis, pharmacokinetics, pharmacology)
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Nude
  • Microsomes, Liver
  • Models, Molecular
  • Mutation
  • Neoplasm Transplantation
  • Phenylurea Compounds (chemical synthesis, pharmacokinetics, pharmacology)
  • Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics)
  • Quinazolines (chemical synthesis, pharmacokinetics, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Transplantation, Heterologous

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