Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles
Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles
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DOI：
10.1021/jm0495935
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发表时间：
2005-03-24
影响因子：
7.3
通讯作者：
Breitenbucher, JG
中科院分区：
文献类型：
--
作者：
Arienti, KL;Brunmark, A;Breitenbucher, JG
本发明公开了一系列新的、有效的和高选择性的DNA损伤控制激酶Chk2抑制剂的发现。在这里，我们报告了第一个关于该激酶抑制剂的SAR研究。对纯化的人Chk2的高通量筛选导致了一系列新的2-芳基苯并咪唑类激酶抑制剂的鉴定。使用Chk2的同源模型和抑制剂的对接促进了优化，导致了高效的2-芳基苯并咪唑2小时(IC50 15 NM)。化合物2小时是一种ATP竞争性的Chk2抑制剂，剂量依赖地保护人的CD4+和CD8+T细胞免受电离辐射的凋亡。这项工作表明，一种选择性的Chk2小分子抑制剂可能成为放射治疗的有用辅助，增加这种治疗的治疗窗口。
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 (IC50 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.