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.
Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring / Menard, Delphine; Niculescu Duvaz, Ion; Dijkstra, Harmen P; I. Niculescu Duvaz, Dan; Suijkerbuijk, Bart M. J. M.; Zambon, Alfonso; Nourry, Arnaud; Roman, Esteban; Davies, Lawrence; Marine, ; Friedlos, Frank; Helen A., And; Kirk, Ruth and; Gill, Adrian; Whittaker, Steven; Taylor, Richard D; Marais, Richard; Springer, Caroline. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - (2009), pp. 3881-3891. [10.1021/jm900242c]
Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring
ZAMBON, Alfonso;
2009
Abstract
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.
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