Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): increasing cellular potency through optimization of a distal heteroaromatic group.

BM Suijkerbuijk, I Niculescu-Duvaz, C Gaulon, HP Dijkstra, D Niculescu-Duvaz, D Ménard, A Zambon, A Nourry, L Davies, HA Manne, F Friedlos, CJ Springer

Research output: Contribution to journalArticlepeer-review

Abstract

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A−B−C system (where A is a hinge binding pyrido[4,5-b]imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified V600EBRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated V600EBRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, V600EBRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo.
Original languageEnglish
Pages (from-to)2741-2756
Number of pages16
JournalJournal of Medicinal Chemistry
Volume53
Issue number7
DOIs
Publication statusPublished - Apr 2010

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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