• BRAF IC50 = 1 nm; pERK = 610 nM; SRB GI50 = 470 nM
OTAVAchemicals Catalogue Number: 7070707132
CAS Registry Number: 884339-61-1
Purity: 95%+ (HPLC)
Ref.: Springer et al. Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring. Journal of Medicinal Chemistry (2009), 52, 3881-3891.
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.