MeĢnard, Delphine Niculescu-Duvaz, Ion Dijkstra, Harmen P. Niculescu-Duvaz, Dan M. J. M. Suijkerbuijk, Bart Zambon, Alfonso Nourry, Arnaud Roman, Esteban Davies, Lawrence Manne, Helen A. Friedlos, Frank Kirk, Ruth Whittaker, Steven Gill, Adrian Taylor, Richard D. Marais, Richard Springer, Caroline J. Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring 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 1<i>H</i>-imidazo[4,5-<i>b</i>]pyridine-2(3<i>H</i>)-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 <sup>V600E</sup>BRAF 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 IC<sub>50</sub> of 1 nM for purified <sup>V600E</sup>BRAF and nanomolar activity in cells. binding moiety;MAPK pathway;V 600EBRAF kinase activity;nanomolar activity;oncogenic BRAF;1 nM;RAS;phenyl rings C;protein kinase;allosteric binding site;V 600EBRAF;compound;1 nM Compounds;phenyl ring B;IC 50;Central Phenyl RingBRAF;Novel Potent BRAF Inhibitors;melanoma cells;phenyl ring 2009-07-09
    https://acs.figshare.com/articles/journal_contribution/Novel_Potent_BRAF_Inhibitors_Toward_1_nM_Compounds_through_Optimization_of_the_Central_Phenyl_Ring/2844376
10.1021/jm900242c.s001