Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

  • ACS Med Chem Lett. 2011 Mar 8;2(5):342-7. doi: 10.1021/ml200025q.
Steve Wenglowsky  1 ,  Li Ren  1 ,  Kateri A Ahrendt  1 ,  Ellen R Laird  1 ,  Ignacio Aliagas  2 ,  Bruno Alicke  2 ,  Alex J Buckmelter  1 ,  Edna F Choo  2 ,  Victoria Dinkel  1 ,  Bainian Feng  2 ,  Susan L Gloor  1 ,  Stephen E Gould  2 ,  Stefan Gross  1 ,  Janet Gunzner-Toste  2 ,  Joshua D Hansen  1 ,  Georgia Hatzivassiliou  2 ,  Bonnie Liu  2 ,  Kim Malesky  2 ,  Simon Mathieu  2 ,  Brad Newhouse  1 ,  Nicholas J Raddatz  1 ,  Yingqing Ran  2 ,  Sumeet Rana  1 ,  Nikole Randolph  1 ,  Tyler Risom  1 ,  Joachim Rudolph  2 ,  Scott Savage  2 ,  LeAnn T Selby  1 ,  Michael Shrag  1 ,  Kyung Song  2 ,  Hillary L Sturgis  1 ,  Walter C Voegtli  1 ,  Zhaoyang Wen  2 ,  Brandon S Willis  1 ,  Richard D Woessner  1 ,  Wen-I Wu  1 ,  Wendy B Young  2 ,  Jonas Grina  1
Affiliations
  • 1. Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
  • 2. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.
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.

Keywords
B-RafV600E; MAPK pathway; amorphous spray-dried dispersion; pyrazolopyridine; targeted therapy.