Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure-Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept

J Med Chem. 2018 Aug 23;61(16):7261-7272. doi: 10.1021/acs.jmedchem.8b00782. Epub 2018 Aug 7.

Abstract

Structure-activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors*
  • Activin Receptors, Type I / chemistry
  • Activin Receptors, Type I / metabolism
  • Cell Line
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Humans
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Quinazolinones / chemistry*
  • Structure-Activity Relationship*

Substances

  • Protein Kinase Inhibitors
  • Quinazolinones
  • ACVR1 protein, human
  • Activin Receptors, Type I