人皮瓣内切酶 1 (FEN1)，作为一种结构特异型的5’-核酸酶，在DNA复制和修复系统中起着重要的作用。FEN1在多种癌细胞中高表达，并与癌症的发生与进展密切相关。癌细胞中某些DNA修复元素的上调是对放化疗策略产生抵抗和耐药的重要原因之一，是癌症治疗的瓶颈。基于合成致死性的抗癌原理，本课题组前期研究表明，下调癌细胞中FEN1的表达可抑制癌细胞的增殖，并增加其对替莫唑胺的敏感度；设计合成的FEN1小分子抑制剂能够抑制癌细胞增殖和侵袭，并促进癌细胞凋亡。本研究将根据FEN1蛋白质结构及作用机制设计、合成、筛选和结构优化以获得高效的FEN1小分子抑制剂，探讨其构效关系；阐明其 (单独使用或者联合其他类抗癌药物) 对癌细胞增殖、凋亡和自噬的影响及相关分子机制；探索FEN1小分子抑制剂的体内抗癌活性和作用机制。本研究将为获得高效、安全、靶向的新型抗肿瘤药提供理论和物质基础。

Human flap endonuclease 1 (FEN1), as a member of 5’-nuclease family, is a key enzyme in DNA replication and damage repair systems. It is highly over-expressed in some types of tumors and plays crucial role in tumorigenesis and development. Some up-regulated DNA repair elements generate resistance against radiotherapy and chemotherapy strategies, which is the bottleneck for cancer therapeutics. Based on synthetic lethality theory, our preliminary tests have validated that knockdown of FEN1 is able to inhibit cell proliferation and sensitise Temozolomide. Also, the designed and synthesised FEN1 small molecule inhibitors are able to suppress cancer cell proliferation and invasion; to promote cancer cell apoptosis. This project will perform structural-based design, synthesis, screening and optimisation of FEN1 inhibitors together with structure-activity relationship (SAR) discussions; to illustrate the impact of these inhibitors on tumor cell proliferation, apoptosis and autophagy; to study the in vivo anti-cancer activity and molecular mechanisms. This project will provide both theoretical and physical basis for development of novel targeted anti-cancer agents with high efficacy and safety.