RESUMO
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.
Assuntos
Benzimidazóis/síntese química , Éteres Fenílicos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Protetores contra Radiação/síntese química , Trifosfato de Adenosina/química , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos da radiação , Quinase do Ponto de Checagem 2 , Dano ao DNA , Raios gama , Humanos , Técnicas In Vitro , Modelos Moleculares , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Proteínas Serina-Treonina Quinases/química , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Relação Estrutura-AtividadeRESUMO
In a recent paper, [Arienti, K. L.; Brunmark, A.; Axe, F. U.; McClure, K. M.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.; Chennagiri, R. P.; Karlsson, L.; Brietenbucher, J. G. J. Med. Chem.2005, 48, 1873], we described the discovery of a class of benzimidazole chk2 kinase inhibitors, exemplified by compound 1, which had radio-protective effects in human T-cells subjected to ionizing radiation. Here, a series of non-benzimidazole analogs intended to define the scope of the SAR about this new series of inhibitor, and allow for refinement of the binding model of these compounds to the chk2 kinase is described.