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

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.