Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors

Justin Dietrich, Vijay Gokhale, Xiadong Wang, Laurence H. Hurley, Gary A. Flynn

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

B-Raf protein kinase, which is a key signaling molecule in the RAS-RAF-MEK-ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Here, we present efficient and versatile chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.

Original languageEnglish (US)
Pages (from-to)292-304
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2010

Keywords

  • Allosteric
  • B-Raf
  • Kinase inhibitor
  • Structure-base design
  • Type-II
  • de novo
  • p38

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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