Imidazo[4,5-b]pyridine inhibitors of B-Raf kinase |
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| Authors: | Bradley J. Newhouse Steve Wenglowsky Jonas Grina Ellen R. Laird Walter C. Voegtli Li Ren Kateri Ahrendt Alex Buckmelter Susan L. Gloor Nathalie Klopfenstein Joachim Rudolph Zhaoyang Wen Xianfeng Li Bainian Feng |
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| Affiliation: | 1. Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA;2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA |
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| Abstract: | 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, αC-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. |
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| Keywords: | B-Raf Imidazopyridine Scaffold hopping DFG-in αC-helix out |
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