2. Academic Validation
  3. Discovery and optimization of a novel series of potent mutant B-Raf(V600E) selective kinase inhibitors

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

Affiliation

  • 1 Oncology iMED, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. melissa.vasbinder@astrazeneca.com
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.

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