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

Article abstract of 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-arylbenz-imidazole 2h (IC₅₀ 15 nM). Compound 2h is an ATP-competitive inhibitor of chk2 that dose dependency 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.