Targeting the Fanconi Anemia/Bloom Dissolvasome protein interface as a discovery

将范可尼贫血/布卢姆溶解体蛋白界面作为一项发现

基本信息

批准号：
8569071
负责人：
James L Keck
金额：
$ 19.29万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8569071
关键词：
Affinity Binding Binding Sites Biochemical Biological Biological Assay Bloom Syndrome Cancer cell line Cancerous Cell Line Cell Survival Cells Cellular Structures Chemicals Complex Computer Simulation Coupled DNA DNA Damage DNA Repair DNA Repair Pathway DNA Single Strand Break DNA repair protein Development Docking Epithelial ovarian cancer Fanconi&apos s Anemia Future Genes Genome Stability Genomic Instability Genomics Growth Hereditary Disease Human Cell Line In Vitro Individual Knowledge Lead Libraries Link Malignant Neoplasms Maps Measures Mediating Molecular Mutation Nature Pathway interactions Peptides Poly(ADP-ribose) Polymerases Positioning Attribute Predisposition Proteins Radiation Radiation therapy Repair Complex Roentgen Rays Sister Chromatid Exchange Site Specificity Structure Testing Therapeutic Topoisomerase III Toxic effect abstracting base cancer cell cancer therapy experience genome-wide helicase homologous recombination human DNA in vivo inhibitor/antagonist innovation novel public health relevance repaired screening small molecule success virtual

Affinity Binding Binding Sites Biochemical Biological Biological Assay Bloom Syndrome Cancer cell line Cancerous Cell Line Cell Survival Cells Cellular Structures Chemicals Complex Computer Simulation Coupled DNA DNA Damage DNA Repair DNA Repair Pathway DNA Single Strand Break DNA repair protein Development Docking Epithelial ovarian cancer Fanconi&apos s Anemia Future Genes Genome Stability Genomic Instability Genomics Growth Hereditary Disease Human Cell Line In Vitro Individual Knowledge Lead Libraries Link Malignant Neoplasms Maps Measures Mediating Molecular Mutation Nature Pathway interactions Peptides Poly(ADP-ribose) Polymerases Positioning Attribute Predisposition Proteins Radiation Radiation therapy Repair Complex Roentgen Rays Sister Chromatid Exchange Site Specificity Structure Testing Therapeutic Topoisomerase III Toxic effect abstracting base cancer cell cancer therapy experience genome-wide helicase homologous recombination human DNA in vivo inhibitor/antagonist innovation novel public health relevance repaired screening small molecule success virtual

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项目摘要

DESCRIPTION (provided by applicant): Abstract: Several established cancer treatments take advantage of the fact that cancer cells are often more sensitive to DNA damage from chemical and radiation treatment than non-cancer cells. One shortcoming of this approach, however, is that indiscriminant DNA damage can have toxic effects on non-cancer cells, which makes more specific therapeutics that directly target individual DNA repair proteins highly valuable. Recently chemotherapeutics that block activity of the DNA repair protein poly ADP ribose polymerase have shown great promise as more selective genomic destabilization agents. This proposal seeks to extend the range of selective chemotherapeutic DNA repair targets by developing small-molecules that block the critical interface that links two DNA repair complexes, the Fanconi Anemia core complex and the Bloom dissolvasome. We have used X-ray crystallographic, biochemical, and cell biological approaches to reveal the critical nature of this higher-order complex for cellular genomic stability. In this proposal, we will use a high-throughput chemical screen to identify protein interaction inhibitors that disrupt the Fanconi Anemia core complex/Bloom dissolvasome supercomplex. Classical biochemical and structural aproaches will be used to assess the potency and mechanisms of action of the inhibitors and to drive future 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 cancerous human cell lines.

描述（申请人提供）：摘要：几种既定的癌症治疗方法都利用了以下事实：癌细胞通常比非癌细胞对化学和放射治疗的DNA损伤更敏感。然而，这种方法的一个缺点是，不加代的DNA损伤可能会对非癌细胞产生毒性作用，这使得更具体的疗法直接针对单个DNA修复蛋白高度有价值。最近，阻断DNA修复蛋白聚ADP核糖聚合酶活性的化学治疗剂已显示出更有选择性的基因组破坏剂。该提案旨在通过开发小分子来扩展选择性化学治疗DNA修复目标的范围，从而阻止关键界面连接两个DNA修复复合物，Fanconi贫血核心核心复合物和Bloom Dislovasome。我们使用X射线晶体学，生化和细胞生物学方法来揭示此关键的性质细胞基因组稳定性的高阶复合物。在此提案中，我们将使用高通量化学筛选来识别破坏Fanconi贫血核心复合物/Bloom dissolvasome SuperCompex的蛋白质相互作用抑制剂。经典的生化和结构侵蚀将用于评估抑制剂作用的效力和机制，并提高未来的理性铅改善。铅化合物的化学治疗潜力将通过测量其对超复合物修复的特定DNA损伤类型的影响来确定，并通过评估它们是否有选择地抑制癌性人类细胞系的生长。