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Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring

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journal contribution
posted on 09.07.2009, 00:00 by Delphine Ménard, Ion Niculescu-Duvaz, Harmen P. Dijkstra, Dan Niculescu-Duvaz, Bart M. J. M. Suijkerbuijk, Alfonso Zambon, Arnaud Nourry, Esteban Roman, Lawrence Davies, Helen A. Manne, Frank Friedlos, Ruth Kirk, Steven Whittaker, Adrian Gill, Richard D. Taylor, Richard Marais, Caroline J. Springer
BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit V600EBRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified V600EBRAF and nanomolar activity in cells.