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. Epub 2014 Mar 13.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Activation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • 4-methylquinazoline
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Quinazolines
  • AZ-628
  • Proto-Oncogene Proteins B-raf