Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents.

Dan Niculescu-Duvaz, Ion Niculescu-Duvaz, Bart M.J.M. Suijkerbuijk, Delphine Ménard, Alfonso Zambon, Lawrence Davies, Jean-Francois Pons, Steven Whittaker, Richard Marais, Caroline J. Springer

Research output: Contribution to journalArticlepeer-review

Abstract

The RAS–RAF–MEK–ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine–threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM.
Original languageEnglish
Pages (from-to)1284-1304
Number of pages21
JournalBioorganic & Medicinal Chemistry
Volume21
Issue number5
DOIs
Publication statusPublished - 1 Mar 2013

Keywords

  • BRAF
  • Kinase inhibitors
  • Anticancer
  • Melanoma
  • Triarylimidazole

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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