Development of 'DFG-out' inhibitors of gatekeeper mutant kinases

Bioorg Med Chem Lett. 2012 Aug 15;22(16):5297-302. doi: 10.1016/j.bmcl.2012.06.036. Epub 2012 Jun 23.

Abstract

HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Half-Life
  • Hydrogen Bonding
  • Mice
  • Mutation
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Piperazines / toxicity
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / toxicity
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / toxicity

Substances

  • HG-7-85-01 compound
  • HG-7-86-01
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Thiazoles
  • Fusion Proteins, bcr-abl