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

• 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
• 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

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.

摘要 单链DNA修复（ssDR）对于防止基因组灾难至关重要。AnaNeo Therapeutics 由DNA修复机制专家创立。扩展我们团队以前的基本ssDR研究， 分析了> 61，000个肿瘤的体细胞突变，产生了同基因突变体/野生型细胞系对， 两个具有小分子文库的同基因细胞系对，进行了计算和实验合成 致死率（SL）筛选，并使用最先进的Schrodinger Maestro药物对接软件来提名小 分子ssDR SL命中。在这个第一阶段STTR项目中，我们建议验证候选目标和小 分子抑制剂。总的来说，这项研究将提名创新的ssDR SL精确治疗靶点和小 在未来的II期SBIR研究中进行先导化合物优化的分子命中。