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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：
10188462
负责人：
Matthew Kyle Hadden
金额：
$ 50.79万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188462
关键词：
Adjuvant Alkylating Agents Antineoplastic Agents Binding Biochemical Biochemistry Biological Assay Bypass C-terminal Cancer Model Cancer Relapse Cantor Cell model Cells Cellular biology Chemoresistance Chemotherapy-Oncologic Procedure Cisplatin Clinical Oncology Combined Modality Therapy Complex Computer Models Crystallization 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 Multiprotein Complexes Mutagenesis Mutagens Mutation Nature Oncology Outcome Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacists Phenotype Platinum Process Proliferating Property Protein Region Public Health Regimen Relapse Reporting Research Research Personnel Resistance Resistance development Roentgen Rays Series Specificity Structural Biologist Structure Testing Therapeutic Tissues Walkers acquired drug resistance analog anti-cancer anti-cancer therapeutic anticancer activity cancer cell cancer therapy chemotherapy combat design experience genotoxicity human model improved in vivo in vivo Model inhibitor/antagonist interdisciplinary approach mouse model neoplastic cell novel novel strategies prevent protein protein interaction repaired scaffold side effect small molecule small molecule inhibitor structural biology success 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.

铂化剂和烷基化剂是治疗多种人类癌症的标准一线化疗药物。