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

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

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.

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