1160825-37-5Relevant articles and documents
Novel potent BRAF inhibitors: Toward 1 nM compounds through optimization of the central phenyl ring
Ménard, Delphine,Niculescu-Duvaz, Ion,Dijkstra, Harmen P.,Niculescu-Duvaz, Dan,Suijkerbuijk, Bart M. J. M.,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.
experimental part, p. 3881 - 3891 (2010/02/17)
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 V 600EBRAF and nanomolar activity in cells.
