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Targeting Rev1-mediated Translesion Synthesis for Cancer Therapy

靶向 Rev1 介导的跨损伤合成用于癌症治疗

基本信息

批准号：
9099802
负责人：
Jiyong Hong
金额：
$ 16.27万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099802
关键词：
Adjuvant Affinity Antineoplastic Agents Binding Biochemical Biological Biological Assay Bypass C-terminal Cancer Model Cancer Patient Cell Survival Cells Cisplatin Clinical Complex DNA DNA Damage DNA biosynthesis DNA replicase DNA-Directed DNA Polymerase Defense Mechanisms Development Disease Dominant-Negative Mutation Drug resistance Effectiveness Enzyme-Linked Immunosorbent Assay Evaluation Family Genomics Goals Health In Vitro Investigation Lead Lesion Malignant Neoplasms Mammalian Cell Maps Mediating Molecular Mus Mutagenesis Nucleotides Outcome Pathway interactions Pharmaceutical Preparations Phenotype Play Point Mutation Polymerase Population Primer Extension Process Protein Analysis RNA Relapse Role Scaffolding Protein Site Solubility Structure-Activity Relationship Therapeutic Therapeutic Effect Titrations Transferase Treatment outcome Yeasts acquired drug resistance analog base biophysical properties cancer cell cancer therapy chemotherapy cost effective therapy improved in vivo ineffective therapies inhibitor/antagonist insight novel pharmacophore prevent scaffold small molecule tumor

项目摘要

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.

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，它使 DNA 能够跨损伤部位复制，从而以复制保真度为代价促进细胞存活。这一过程直接有助于化疗后癌细胞的存活和癌症耐药性的发展。真核 Y 家族聚合酶 Rev1 是跨损伤合成中重要的支架蛋白，其 C 端结构域 (CTD) 与跨损伤聚合酶 、、 和  相互作用，是功能所必需的。最近的生化和结构研究揭示了 Rev1 CTD 介导的跨损伤聚合酶复合物组装的分子基础，并且使用小鼠癌症模型的体内研究已确立 Rev1 介导的跨损伤合成作为治疗耐药肿瘤的有希望的新靶点。该提案的目标是开发 Rev1 CTD 的小分子拮抗剂作为新型辅助癌症疗法，以增强 DNA 损伤剂对抗耐药癌症的有效性。这将通过发现、优化和表征先导化合物来实现，这些先导化合物会破坏 Rev1 CTD 在跨损伤合成中的基本支架功能，并证明它们使耐药癌症对 DNA 损伤性化疗药物（如顺铂）敏感的能力。