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Inhibition of Translesion Synthesis as a Novel Strategy for Cancer Chemotherapy

抑制跨损伤合成作为癌症化疗的新策略

基本信息

批准号：
10633088
负责人：
Matthew Kyle Hadden
金额：
$ 49.53万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633088
关键词：
Acceleration Adjuvant Alkylating Agents Antineoplastic Agents Binding Biochemical Biochemistry Biological Assay Bypass C-terminal Cancer Model Cancer Relapse Cantor Cell Proliferation Cell Survival Cell model Cells Cellular biology Chemoresistance Chemotherapy-Oncologic Procedure Cisplatin Clinical Oncology Combined Modality Therapy Complex Computer Models DNA Adduction DNA Adducts DNA Damage DNA Repair DNA biosynthesis DNA-Directed DNA Polymerase Development Disadvantaged Dose Drug Design Drug Kinetics Effectiveness Ensure Exhibits Future Goals Human In Vitro Lead Malignant Neoplasms Mediating Medicine Multiprotein Complexes Mutagenesis Mutagens Mutation Nature Oncology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacists Phenotype Platinum Process Property Protein Region Public Health Regimen Relapse Reporting Research Research Personnel Resistance Resistance development Roentgen Rays Series Specificity Structural Biologist Structure Testing Therapeutic Tissues acquired drug resistance analog anti-cancer anti-cancer therapeutic anticancer activity cancer cell cancer therapy chemotherapy combat experience genotoxicity human model improved in vivo in vivo Model inhibitor interdisciplinary approach mouse model neoplastic cell novel novel strategies prevent protein protein interaction rational design repaired scaffold side effect small molecule small molecule inhibitor structural biology success therapy outcome tumor

项目摘要

Platinating and alkylating agents are standard first-line chemotherapy for many forms of human cancer. Typically, patients initially respond well to these agents; however, many can develop resistance and experience relapse, which requires a change in drug regimen to combat the relapsed cancer. In addition, the high doses of these drugs required for their anti-cancer effects can result in toxic side effects in other tissues throughout the body, limiting both the short- and long-term effectiveness of first-line agents. Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication without repairing the damage. In the context of cancer treatment, TLS promotes survival of tumor cells by allowing replication over platinum and alkyl DNA adducts, which results in increased mutations in surviving tumor cells and acquisition of resistance to the first-line agent. Disruption of TLS sensitizes cancers to genotoxic agents and reduces mutagenesis in tumors, suggesting that combination therapy with an inhibitor of TLS could enhance the efficacy of first-line agents and prevent chemoresistance. As such, small molecule inhibitors of TLS are emerging as a new class of adjuvant agents for first-line cancer chemotherapy. Assembly of the multi-protein complex that mediates TLS is controlled by the DNA polymerase Rev1, which serves as the central scaffold to maintain the complex through multiple protein-protein interactions (PPIs). Several essential steps of TLS are mediated through PPIs between the C-terminal domain of Rev1 (Rev1-CT) and Rev-1 interacting regions (RIR) from multiple TLS DNA polymerases. Previous studies have demonstrated that suppression of Rev1 expression in vitro and in vivo sensitizes cancer cells to genotoxic chemotherapeutics and decreases acquired drug resistance in tumors. Recent collaborative research in our labs has led us to identify the first reported small molecules that inhibit TLS by disrupting the Rev1-CT/RIR PPI through direct binding to Rev1-CT at the RIR interface. These compounds increase cisplatin sensitivity and reduce cisplatin-induced mutagenesis in human cancer cells. Our results demonstrate that the Rev1-CT/RIR interface is a druggable PPI and they validate that its disruption enhances the anti-cancer effects of first-line genotoxic agents. Within this context, the overall goal of our studies is to apply a comprehensive interdisciplinary approach to develop our lead TLS inhibitors as a new class of anti-cancer therapeutics. In pursuit of this goal, we will undertake the following specific aims: (1) synthesize and characterize improved small molecule inhibitors of the Rev1-CT/RIR PPI, (2) evaluate Rev1-CT/RIR inhibitors using in vitro biochemical and structural approaches, (3) probe cellular anti-TLS and anti-cancer activities of the Rev1-CT/RIR inhibitors, and (4) perform in vivo studies on optimal compounds. We anticipate that these studies will identify small molecules with enhanced anti-TLS activity and improved drug-like properties as promising cancer chemotherapeutics.

铂化剂和烷化剂是许多形式的人类癌症的标准一线化疗。通常情况下，患者最初对这些药物反应良好;然而，许多人可能会产生耐药性，并出现复发，这需要改变药物方案以对抗复发的癌症。此外，高剂量的这些抗癌作用所需的药物可在整个组织中导致毒副作用这限制了一线药物的短期和长期有效性。翻译合成（TLS）是一种增殖细胞在复制过程中耐受DNA损伤而不修复的重要机制造成的伤害在癌症治疗的背景下，TLS通过允许复制超过铂和烷基DNA加合物，导致存活肿瘤细胞突变增加，对一线药剂的抵抗。TLS的破坏使癌症对遗传毒性剂敏感，突变，表明与TLS抑制剂的联合治疗可以提高疗效并预防耐药性。因此，TLS的小分子抑制剂正在成为一种新的治疗方法。用于一线癌症化疗的新型辅助剂。介导TLS的多蛋白复合物的组装由DNA聚合酶Rev 1控制，作为中心支架，通过多种蛋白质-蛋白质相互作用（PPI）维持复合物。 TLS的几个基本步骤通过PPI介导，在Rev 1的C-末端结构域（Rev 1-CT）之间和来自多种TLS DNA聚合酶的Rev-1相互作用区（RIR）。先前的研究已经证明在体外和体内抑制Rev 1表达可使癌细胞对遗传毒性化疗药物敏感并降低肿瘤中获得性耐药性。我们实验室最近的合作研究使我们确定了第一个报道的小分子通过直接结合破坏Rev 1-CT/RIR PPI抑制TLS，版本1-RIR接口处的CT。这些化合物增加顺铂敏感性并减少顺铂诱导的细胞毒性。在人类癌细胞中的诱变。我们的研究结果表明，Rev 1-CT/RIR接口是一种可药物化的PPI 并且他们证实其破坏增强了一线遗传毒性剂的抗癌作用。在这背景下，我们的研究的总体目标是应用全面的跨学科方法来发展我们的引领TLS抑制剂成为一类新的抗癌治疗剂。为了实现这一目标，我们将以下具体目标：（1）合成和表征Rev 1-CT/RIR的改进的小分子抑制剂， PPI，（2）使用体外生物化学和结构方法评价Rev 1-CT/RIR抑制剂，（3）探测细胞 Rev 1-CT/RIR抑制剂的抗TLS和抗癌活性，以及（4）对最佳的抗TLS和抗癌活性进行体内研究。化合物.我们预计这些研究将鉴定出具有增强的抗TLS活性的小分子，作为有前景的癌症化疗剂的改善的药物样性质。