2. Academic Validation
  3. Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase

Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase

  • Bioorg Med Chem Lett. 2014 Apr 15;24(8):1923-7. doi: 10.1016/j.bmcl.2014.03.007.
Steve Wenglowsky 1,  Li Ren 2,  Jonas Grina 1,  Joshua D Hansen 1,  Ellen R Laird 1,  David Moreno 1,  Victoria Dinkel 1,  Susan L Gloor 1,  Gregg Hastings 1,  Sumeet Rana 1,  Kevin Rasor 1,  Hillary L Sturgis 1,  Walter C Voegtli 1,  Guy Vigers 1,  Brandon Willis 1,  Simon Mathieu 3,  Joachim Rudolph 3
Affiliations

Affiliations

  • 1 Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States.
  • 2 Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, United States. Electronic address: li.ren@arraybiopharma.com.
  • 3 Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080-4990, United States.
PMID: 24675381 DOI: 10.1016/j.bmcl.2014.03.007
Abstract

Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf Inhibitor, a finding that should have broad application in kinase drug discovery.

Keywords

B-Raf inhibitors; Kinase drug discovery; Melonoma; Type IIB inhibitor.

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