Identification and characterisation of 2-aminopyridine inhibitors of checkpoint kinase 2

Bioorg Med Chem. 2010 Jan 15;18(2):707-18. doi: 10.1016/j.bmc.2009.11.058. Epub 2009 Dec 6.

Abstract

5-(Hetero)aryl-3-(4-carboxamidophenyl)-2-aminopyridine inhibitors of CHK2 were identified from high throughput screening of a kinase-focussed compound library. Rapid exploration of the hits through straightforward chemistry established structure-activity relationships and a proposed ATP-competitive binding mode which was verified by X-ray crystallography of several analogues bound to CHK2. Variation of the 5-(hetero)aryl substituent identified bicyclic dioxolane and dioxane groups which improved the affinity and the selectivity of the compounds for CHK2 versus CHK1. The 3-(4-carboxamidophenyl) substituent could be successfully replaced by acyclic omega-aminoalkylamides, which made additional polar interactions within the binding site and led to more potent inhibitors of CHK2. Compounds from this series showed activity in cell-based mechanistic assays for inhibition of CHK2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry
  • Aminopyridines / pharmacology*
  • Binding Sites
  • Cell Line
  • Checkpoint Kinase 2
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Aminopyridines
  • Protein Kinase Inhibitors
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein Serine-Threonine Kinases
  • alpha-aminopyridine