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.