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Small molecule inhibitors as a new approach to study human RAD51 recombinase

小分子抑制剂作为研究人类 RAD51 重组酶的新方法

基本信息

批准号：
9762019
负责人：
ALEXANDER V MAZIN
金额：
$ 35.81万
依托单位：
DREXEL UNIVERSITY
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：
2019-09-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762019
关键词：
Ablation Animal Model Apoptosis Base Excision Repairs Biochemical Biological Biological Assay Biology Biophysics Cancer Patient Cell Cycle Checkpoint Cell Survival Cell model Cell physiology Cells Chickens Collection Combined Modality Therapy Complement Complex Cruciform DNA Crystallography DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA lesion Development Docking Dose Genetic Diseases Genomic Instability Goals Healthcare Homologous Protein Human In Vitro Individual Knowledge Measures Modernization Molecular Mus Mutate Mutation Names Nonhomologous DNA End Joining Normal Cell Organism Pathway interactions Play Proliferating Property Proteins Rad51 recombinase Radiation Radiation therapy Radio Reaction Role Specificity Structure Therapeutic Therapeutic Agents Time Xenograft procedure analog cancer cell cancer genetics cancer therapy cell killing cellular development chemotherapeutic agent chemotherapy combination cancer therapy crosslink experimental study genetic approach high throughput screening homologous recombination improved in vivo inhibitor/antagonist migration mutant novel novel strategies protein function prototype public health relevance repaired response small molecule small molecule inhibitor tool tumor

项目摘要

DESCRIPTION (provided by applicant): The homologous recombination (HR) pathway plays a critical role in the repair of the most harmful DNA lesions, DNA double-strand breaks (DSB) and inter-strand cross-links (ICL). Malfunction of HR causes genome instability, cancer, and genetic diseases. RAD51, a key HR protein, promotes DNA strand exchange, a basic step of HR. However, the mechanism of DNA strand exchange and specific functions of RAD51 in human cells remain to be elucidated. Traditional genetic approaches are difficult to apply because RAD51 is essential for cell viability. Here, we propose to develop small molecule inhibitors to study RAD51 activities and functions. These inhibitors may also be used as prototypes for development of combination therapies to sensitize cancer cells for radiation and chemotherapy. Because millions of cancer patients commonly undergo radiation therapy and chemotherapy, improvement of their efficacy will have a significant impact on the public healthcare. Small molecule compounds (MW < 500 Da) that can perturb specific functions of proteins became an important tool in modern biology. Small molecule inhibitors act rapidly and often reversibly. They can be introduced at any point of organism or cell development and applied in a dose-dependent manner, which is especially important in studies of proteins essential for cell viability, like RAD51. Previously, by high throughput screening we identified several small molecule inhibitors of RAD51 and demonstrated for the first time their biological activity in the cell. Here, we will use these inhibitors to analyze the mechanism of RAD51 DNA strand exchange and the functions of RAD51 in human cells. Using cellular and animal models we will explore the ability of the RAD51 inhibitors alone or in combination with inhibitors of othe DNA repair pathways to increase killing of cancer cells by chemotherapeutic agents.

描述（由申请人提供）：同源重组（HR）途径在修复最有害的DNA损伤、DNA双链断裂（DSB）和链间交联（ICL）中起关键作用。HR的功能障碍会导致基因组不稳定、癌症和遗传疾病。RAD51是一种重要的HR蛋白，它促进DNA链交换，这是HR的一个基本步骤，然而，DNA链交换的机制以及RAD51在人类细胞中的具体功能仍有待阐明。传统的遗传学方法很难应用，因为RAD51对细胞活力至关重要。在此，我们建议开发小分子抑制剂来研究RAD 51的活性和功能。这些抑制剂也可用作开发联合疗法的原型，以使癌细胞对放射和化学疗法敏感。由于数以百万计的癌症患者通常接受放射治疗和化学治疗，提高其疗效将对公共医疗产生重大影响。分子量小于500 Da的小分子化合物可以干扰蛋白质的特定功能，已成为现代生物学研究的重要工具。小分子抑制剂作用迅速且通常可逆。它们可以在生物体或细胞发育的任何点引入，并以剂量依赖性方式应用，这在细胞活力所必需的蛋白质（如RAD 51）的研究中尤其重要。此前，通过高通量筛选，我们鉴定了几种小分子的RAD51抑制剂，并首次证明了它们在细胞中的生物活性。在此，我们将使用这些抑制剂来分析RAD51 DNA链交换的机制以及RAD51在人类细胞中的功能。使用细胞和动物模型，我们将探索单独或与其他DNA修复途径的抑制剂组合的RAD51抑制剂增加化疗剂对癌细胞的杀伤的能力。