Targeting Rev1-mediated Translesion Synthesis for Cancer Therapy

 描述(由申请人提供)：跨损伤合成是一种基本的细胞防御机制，使DNA能够跨病变部位复制，以促进细胞存活，代价是复制的保真度。这一过程直接促进了肿瘤细胞的存活和化疗后肿瘤耐药的发展。真核细胞Y-家族聚合酶Rev1是跨损伤合成过程中必不可少的支架蛋白，其C-末端结构域与跨损伤聚合酶，，和相互作用是必需的。最近的生化和结构研究揭示了Rev1 CTD介导的跨病变聚合酶复合体组装的分子基础，使用小鼠癌症模型的体内研究已经建立了Rev1介导的跨病变合成作为治疗耐药肿瘤的一个有前途的新靶点。这项建议的目标是开发Rev1 CTD的小分子拮抗剂作为新的癌症辅助治疗药物，以增强DNA损伤剂对耐药癌症的疗效。这将通过发现、优化和表征破坏Rev1 CTD在跨病变合成中的基本支架功能的先导化合物来实现，并通过展示它们使耐药癌症对DNA破坏性化疗药物(如顺铂)敏感的能力来实现。

 DESCRIPTION (provided by applicant):Translesion synthesis is a fundamental cellular defense mechanism that enables DNA replication across lesion sites in order to promote cell survival at the cost of replication fidelity. Such a process directly contributes to cancer cell survival and the development of cancer drug resistance after chemotherapy. The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in translesion synthesis, and its C-terminal domain (CTD), which interacts with translesion polymerases , ,  and , is absoltely required for function. Recent biochemical and structural investigations have revealed the molecular basis of the Rev1 CTD-mediated assembly of translesion polymerase complexes, and in vivo studies using murine cancer models have established Rev1-mediated translesion synthesis as a promising new target for treatment of drug-resistant tumors. The goal of this proposal is to develop small molecule antagonists of the Rev1 CTD as novel adjuvant cancer therapeutics to enhance the effectiveness of DNA-damaging agents against drug-resistant cancers. This will be achieved by discovery, optimization, and characterization of lead compounds that disrupt the essential scaffolding function of the Rev1 CTD in translesion synthesis and by demonstrating their ability to sensitize drug-resistant cancers to DNA-damaging chemotherapeutics, such as cisplatin.