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

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 (V600E)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(50) of 1 nM for purified (V600E)BRAF and nanomolar activity in cells.

Design, synthesis and evaluation of novel 2-(1H-imidazol-2-yl) pyridine Sorafenib derivatives as potential BRAF inhibitors and anti-tumor agents

“…They were tested at the concentration of 10 mM against six human cancer cell lines, representing different tumor types, namely human liver cancer cell line (HepG2), human breast cancer cell lines (MDA-MB-453 and MCF-7), human intestinal caner cell line (SW480), human melanoma cancer cell line (A375) and lung cancer (H522). As shown in Table 3, compounds CLW14, 15,22,27, 31 demonstrated evident antiproliferation effects with inhibition percentages higher than 50% for HepG2. It is worth pointing out that significant inhibition was achieved for compounds CLW01, 03, 14,15,16,17,18,22,27,28 against A375 with an inhibition percentage higher than 40%.…”

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

“…23 In their work, they proposed an analogous binding mode of their compounds to V600E BRAF based on the crystal structure of wild-type BRAF with sorafenib, and in doing so, they were able to exploit a lipophilic pocket in the binding site which would be available to accommodate the newly introduced ring substituents. All but two of the compounds prepared possessed activity that inhibited the oncogenic BRAF mutation, and in particular compounds 2 and 3 possessed IC50 values of 1nM, results which clearly demonstrate the importance of these ring modifications in being able to inhibit V600E BRAF selectively.…”

Pharmacophore model generation and 3D-QSAR analysis of N-acyl and N-aroylpyrazolines for enzymatic and cellular B-Raf kinase inhibition

“…There are also a number of other scaffolds available such as disubstituted Pyrazine (Niculescu-Duvaz et al, 2008). Pyridopyrazinone (Zambon et al, 2010), Benzimidazole (Ramurthy et al, 2008), Pyrazolylpyrrole (Aronov et al, 2007), and 1H-imidazo[4,5-b]pyridine-2(3H)-one (Ménard et al, 2009) for B-Raf kinase inhibition; however, substituted pyrazoles exhibit a range of diversity in the structures as well as in biological activities so this series of molecules is good for generating the significant quantitative relationship.…”