DNA交联损伤修复是癌细胞对DNA交联药物产生耐药性的重要原因之一。最新研究表明范可尼贫血互补蛋白M（FANCM）的DNA转位酶功能在DNA交联损伤修复中起着关键作用，DNA转位酶FANCM可能成为解决DNA交联药物耐药性问题的潜在靶点。因此，利用化学小分子抑制FANCM的DNA转位酶活性可成为解决DNA交联药物耐药性的新手段。目前尚无关于高通量筛选FANCM转位酶抑制剂方法的报道，我们的前期研究表明三链DNA解旋反应能为检测FANCM转位酶抑制剂活性提供可能性。本项目拟在SAMDI技术上引入三链DNA解旋反应，从小分子化合物库中高通量筛选FANCM转位酶抑制剂，并对其结构进行优化；在细胞水平探讨FANCM转位酶抑制剂对DNA交联损伤修复通路的影响以及对DNA交联药物耐药性的影响。本项目的完成将为研究DNA转位酶FANCM的生物学功能提供分子工具，并为改善DNA交联药物耐药性提供新策略。

DNA crosslink repair is one of the important reasons that cancer cells develop drug resistance to DNA crosslinking reagents. Recent studies have shown DNA translocase activity of Fanconi anemia complementation group M (FANCM) plays a significant role in DNA crosslink repair process. FANCM is identified as a potential target to solve the resistance issue of DNA crosslinking drugs. Therefore, using small molecules to inhibit DNA translocase activity has potential to be a novel strategy to solve the drug resistance problem. Currently, high-throughput screening method of FANCM DNA translocase inhibitor has not been reported. Our previous study shows the triple helix displacement assay may offer a possibility to determine the inhibition of DNA translocase activity. In this project, we will utilize a high-throughput screening method based on SAMDI technique to screen DNA translocase inhibitor of FANCAM from a compound library, and modify inhibitor’s structure. Furthermore, we will study the impact of DNA translocase inhibitors on DNA crosslink repair pathway and drug resistance of DNA crosslinking reagents. The completion of this project will provide a small molecule tool for the study of FANCM’s biological function and novel strategy to address crosslinking drug tolerance issues.