Structure-based design and optimization of 2-aminothiazole-4-carboxamide as a new class of CHK1 inhibitors

Bioorg Med Chem Lett. 2013 May 1;23(9):2590-4. doi: 10.1016/j.bmcl.2013.02.108. Epub 2013 Mar 7.

Abstract

Drug design efforts in the emerging 2-aminothiazole-4-carboxamide class of CHK1 inhibitors have uncovered specific combinations of key substructures within the molecule; resulting in significant improvements in cell-based activity while retaining a greater than one hundred-fold selectivity against CDK2. The X-ray crystal structure of a complex between compound 39 and the CHK1 protein detailing a 'U-shaped' topology and key interactions with the protein surface at the ATP site is also reported.

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / metabolism
  • Binding Sites
  • Checkpoint Kinase 1
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / metabolism
  • Drug Design*
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinases / chemistry*
  • Protein Kinases / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry*

Substances

  • Amides
  • Protein Kinase Inhibitors
  • Thiazoles
  • 2-aminothiazole
  • Protein Kinases
  • Checkpoint Kinase 1
  • Cyclin-Dependent Kinase 2