National Center for
4MBJ: Human B-raf Kinase Domain In Complex With An Imidazopyridine-based Inhibitor
Bioorg. Med. Chem. Lett. (2013) 23 p.5896-5899
This Letter details the synthesis and evaluation of imidazo[4,5-b]pyridines as inhibitors of B-Raf kinase. These compounds bind in a DFG-in, alphaC-helix out conformation of B-Raf, which is a binding mode associated with significant kinase selectivity. Structure-activity relationship studies involved optimization of the ATP-cleft binding region of these molecules, and led to compound 23, an inhibitor with excellent enzyme/cell potency, and kinase selectivity.