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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：
8888191
负责人：
ALEXANDER V MAZIN
金额：
$ 48.92万
依托单位：
DREXEL 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：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8888191
关键词：
Ablation Affect Animal Model Apoptosis Base Excision Repairs Biochemical Biological Biological Assay Biology Cancer Patient Cell Cycle Checkpoint Cell Survival Cell model Cell physiology Cells Chickens Collection Combined Modality Therapy Complex Cruciform DNA Crystallography DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA biosynthesis DNA lesion Development Docking Dose Genomic Instability Goals Healthcare Hereditary Disease Human In Vitro Individual Inhibitory Concentration 50 Knowledge Measures Molecular Mus Mutate Mutation Names Nonhomologous DNA End Joining Normal Cell Organism Pathway interactions Play Proliferating Property Proteins Radiation Radiation therapy Reaction Role Specificity Structure Therapeutic Therapeutic Agents Time XRCC3 gene Xenograft procedure analog cancer cell cancer genetics cancer therapy cell killing cellular development chemotherapeutic agent chemotherapy combination cancer therapy crosslink genetic approach high throughput screening homologous recombination improved in vivo inhibitor/antagonist killings migration mutant novel novel strategies protein function prototype public health relevance recombinase repaired research study response small molecule 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.