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Identification of chemosensitizing agents that block DNA repair by the Fanconi Anemia/Bloom Dissolvasome complex

鉴定通过范可尼贫血/布卢姆溶解体复合物阻断 DNA 修复的化学增敏剂

基本信息

批准号：
9191106
负责人：
Andrew Ford Voter
金额：
$ 3.35万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191106
关键词：
Adjuvant Affinity Binding Binding Sites Biochemical Biological Bloom Syndrome C-terminal Cancer cell line Cell Line Cells Chemicals Clinical Complex Computer Simulation DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway Development Docking Fanconi Anemia pathway Fanconi&apos s Anemia Genes Genome Stability Genomic Instability Growth Hereditary Disease Human Human Cell Line Hypersensitivity Immune In Vitro Individual Lead Length Libraries Link Malignant Neoplasms Maps Measurement Measures Mediating Modality Mutation Nature Pathway interactions Peptides Pilot Projects Poly(ADP-ribose) Polymerases Predisposition Proteins Radiation therapy Repair Complex Resistance Roentgen Rays Sister Chromatid Exchange Site Specificity Structure-Activity Relationship Testing Therapeutic Topoisomerase Toxic effect Up-Regulation abstracting cancer cell cancer therapy chemosensitizing agent crosslink genome-wide helicase high throughput screening in vivo inhibitor/antagonist new therapeutic target novel protein protein interaction repaired research study scaffold small molecule small molecule inhibitor success therapeutic target therapy resistant tumor

项目摘要

Abstract: Several established cancer treatments take advantage of the hypersensitivity of cancer cells to DNA damage by inducing genome-wide damage to cellular DNA. However, tumors often evolve resistance to DNA-damaging chemotherapeutics by elevating the activities of DNA repair pathways, becoming dependent on specific repair activities for survival. These observations make therapeutics that selectively target individual DNA repair proteins, especially those involved in therapeutic resistance, highly valuable. Inhibitors that block activity of the DNA repair protein poly-ADP ribose polymerase are one example of specific repair inhibitors that show great promise as chemotherapeutics. This proposal extends this approach to target a novel chemotherapeutic DNA repair pathway by developing small-molecules that block the critical interface linking two DNA repair complexes known to be involved in tumor chemotherapeutic resistance -- the Fanconi Anemia complex and the Bloom Dissolvasome. X-ray crystallographic, biochemical, and cell biological approaches have revealed the critical nature of this higher-order complex for cellular genomic stability and its promise as a novel therapeutic target. In addition, I have developed an excellent high throughput screening ready strategy that has already identified a small number of inhibitors in a pilot study. In this proposal, I will carry out a large-scale high- throughput chemical screen to identify protein-protein interaction inhibitors that disrupt the formation of the Fanconi Anemia-Bloom Dissolvasome supercomplex. Biochemical, structural, and cellular approaches will be used to assess the potency and mechanisms of action of the inhibitors and to drive rational lead improvement. The chemotherapeutic potential of the lead compounds will be determined by measuring their effects on the specific types of DNA damage repaired by the supercomplex and by assessing whether they selectively inhibit growth of human cancer cell lines as monotherapies and as adjuvants with clinical chemotherapeutics.

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