Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors

  • J Med Chem. 2013 Mar 14;56(5):1996-2015. doi: 10.1021/jm301658d.
Melissa M Vasbinder  1 ,  Brian Aquila ,  Martin Augustin ,  Huawei Chen ,  Tony Cheung ,  Donald Cook ,  Lisa Drew ,  Benjamin P Fauber ,  Steve Glossop ,  Michael Grondine ,  Edward Hennessy ,  Jeffrey Johannes ,  Stephen Lee ,  Paul Lyne ,  Mario Mörtl ,  Charles Omer ,  Sangeetha Palakurthi ,  Timothy Pontz ,  Jon Read ,  Li Sha ,  Minhui Shen ,  Stefan Steinbacher ,  Haixia Wang ,  Allan Wu ,  Minwei Ye
Affiliations
  • 1. Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. [email protected]
PMID: 23398453 DOI: 10.1021/jm301658d
Abstract

B-Raf represents an attractive target for Anticancer therapy and the development of small molecule B-Raf inhibitors has delivered new therapies for metastatic melanoma patients. We have discovered a novel class of small molecules that inhibit mutant B-Raf(V600E) kinase activity both in vitro and in vivo. Investigations into the structure-activity relationships of the series are presented along with efforts to improve upon the cellular potency, solubility, and pharmacokinetic profile. Compounds selectively inhibited B-Raf(V600E) in vitro and showed preferential antiproliferative activity in mutant B-Raf(V600E) cell lines and exhibited selectivity in a kinase panel against Other kinases. Examples from this series inhibit growth of a B-Raf(V600E) A375 xenograft in vivo at a well-tolerated dose. In addition, aminoquinazolines described herein were shown to display PERK elevation in nonmutant B-Raf cell lines in vitro.