An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity.
An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity.
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DOI：
10.1021/jm301565b
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Connell, Philip P.
中科院分区：
文献类型：
--
作者：
Budke, Brian;Kalin, Jay H.;Pawlowski, Michal;Zelivianskaia, Anna S.;Wu, Megan;Kozikowski, Alan P.;Connell, Philip P.
同源重组（HR）是细胞中修复DNA双链断裂和阻碍DNA复制的损伤的重要过程。RAD51是一种进化上保守的蛋白，是HR的核心。RAD51蛋白的过表达在肿瘤细胞中很常见，是肿瘤治疗的潜在靶点。我们之前描述了RAD51的化学抑制剂，称为RI-1（在本报告中称为化合物1）。该化合物的氯马来酰亚胺基团被认为是Michael受体，并与RAD51的C319上的巯基通过共轭加成-消除机制反应。为了减少脱靶效应的可能性并提高化合物在生物系统中的稳定性，我们开发了一种化合物1的类似物，它缺乏基于马来酰亚胺的反应性，但保留了RAD51的抑制活性。这种化合物，1-（3,4-二氯苯基）-3-（4-甲氧基苯基）-4-morpholino- 1h -pyrrole-2,5-dione，命名为RI-2（在本报告中称为化合物7a），似乎与化合物1可逆地结合在RAD51蛋白上的相同位点上。与化合物1一样，化合物7a特异性地抑制人细胞中的HR修复。
Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology. We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report). The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism. In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analog of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity. This compound, 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1. Like compound 1, compound 7a specifically inhibits HR repair in human cells.
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