Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles

J Med Chem. 2005 Mar 24;48(6):1873-85. doi: 10.1021/jm0495935.


The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC(50) 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependently protects human CD4(+) and CD8(+) T-cells from apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of chk2 could be a useful adjuvant to radiotherapy, increasing the therapeutic window of such treatment.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Apoptosis / drug effects
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology
  • Binding Sites
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / radiation effects
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / radiation effects
  • Checkpoint Kinase 2
  • DNA Damage
  • Gamma Rays
  • Humans
  • In Vitro Techniques
  • Models, Molecular
  • Phenyl Ethers / chemical synthesis*
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Radiation-Protective Agents / chemical synthesis*
  • Radiation-Protective Agents / chemistry
  • Radiation-Protective Agents / pharmacology
  • Structure-Activity Relationship


  • 2-(4-(4-chlorophenoxy)phenyl)-1H-benzimidazole-5-carboxylic acid amide
  • Benzimidazoles
  • Phenyl Ethers
  • Radiation-Protective Agents
  • Adenosine Triphosphate
  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases