Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors
ACS Medicinal Chemistry Letters2011Vol. 2(5), pp. 342–347
Citations Over TimeTop 10% of 2011 papers
Steve Wenglowsky, Li Ren, Kateri A. Ahrendt, Ellen R. Laird, Ignacio Aliagas, Bruno Alicke, Alex J. Buckmelter, Edna F. Choo, Victoria Dinkel, Bainian Feng, Susan L. Gloor, Stephen E. Gould, Stefan Groß, Janet Gunzner-Toste, Joshua D. Hansen, Georgia Hatzivassiliou, Bonnie Liu, Kim Malesky, Simon Mathieu, Brad Newhouse, Nicholas J. Raddatz, Yingqing Ran, Sumeet Rana, Nikole Randolph, Tyler Risom, Joachim Rudolph, Scott W. Savage, LeAnn T. Selby, Michael Shrag, Kyung Song, Hillary L. Sturgis, W.C. Voegtli, Zhaoyang Wen, Brandon S. Willis, Richard Woessner, Wen‐I Wu, Wendy B. Young, Jonas Grina
Abstract
The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.
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