Validating novel DNA repair deficient cancer therapy targets and small molecule compounds

验证新型 DNA 修复缺陷癌症治疗靶点和小分子化合物

基本信息

批准号：
10546636
负责人：
Richard Lipkin
金额：
$ 39.89万
依托单位：
ANANEO THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546636
关键词：
Aging Alkylation Aromatic Polycyclic Hydrocarbons Automobile Driving Base Excision Repairs Binding Binding Sites Biological Assay CRISPR screen Cancer Patient Candidate Disease Gene Catalytic Domain Cell Death Cell Line Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Computer software Cytotoxic Chemotherapy D Cells DNA Double Strand Break DNA Repair DNA Repair Disorder DNA Repair Pathway DNA Sequence Alteration DNA lesion DNA-Directed DNA Polymerase Data Docking Double Strand Break Repair Drug Screening ERCC2 gene ERCC6 gene Excision Repair Flow Cytometry Future Gene Mutation Genes Genetic Transcription Genome Genomics Individual Lesion Libraries Malignant Neoplasms Mutation Nonhomologous DNA End Joining Nucleotide Excision Repair Pathway interactions Patients Pharmaceutical Preparations Phase Precision therapeutics RNA Radiation Single-Stranded DNA Small Business Innovation Research Grant Small Business Technology Transfer Research Solid Neoplasm Somatic Mutation Structure-Activity Relationship Therapeutic Toxic effect Uracil base brca gene cancer cell cancer therapy cell type cytotoxicity genome-wide homologous recombination in silico inhibitor innovation lead optimization mutant neoplastic cell novel oxidation precision medicine prevent repaired screening small molecule small molecule inhibitor small molecule libraries targeted cancer therapy targeted treatment tumor tumorigenesis uracil-DNA glycosylase

项目摘要

Abstract Single-strand DNA repair (ssDR) is critical for preventing genomic catastrophe. AnaNeo Therapeutics was founded by experts in DNA repair mechanisms. Extending our team’s previous fundamental ssDR studies we analyzed >61,000 tumors for somatic mutations, generated isogenic mutant/wild-type cell line pairs, screened two isogenic cell line pairs with small molecule libraries, performed computational and experimental synthetic lethality (SL) screens and used state-of-the-art Schrodinger Maestro drug docking software to nominate small molecule ssDR SL hits. Here in this Phase I STTR project we propose to validate candidate targets and small molecule inhibitors. Overall, this study will nominate innovative ssDR SL precision therapy targets and small molecule hits for lead optimization in future Phase II SBIR studies.

抽象的单链 DNA 修复 (ssDR) 对于预防基因组灾难至关重要。由 DNA 修复机制专家创立，扩展了我们团队之前的基础 ssDR 研究。 > 61,000 个肿瘤的体细胞突变，产生同基因突变/野生型细胞系对，并进行筛选两个具有小分子文库的同基因细胞系对，通过计算和实验合成致死率 (SL) 筛选，并使用最先进的薛定谔 Maestro 药物对接软件来提名小型药物分子 ssDR SL 命中。在第一阶段 STTR 项目中，我们建议验证候选目标和小目标。总体而言，这项研究将提名创新的 ssDR SL 精准治疗靶点和小分子抑制剂。未来 II 期 SBIR 研究中先导化合物优化的分子命中。