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

描述（由申请人提供）：摘要：几种已建立的癌症治疗利用了这样一个事实，即癌细胞往往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，不分青红皂白的DNA损伤可能对非癌细胞产生毒性作用，这使得直接靶向单个DNA修复蛋白的更特异性治疗非常有价值。最近，阻断DNA修复蛋白聚ADP核糖聚合酶活性的化疗药物作为更有选择性的基因组去稳定剂显示出很大的前景。该提案旨在通过开发阻断连接两个DNA修复复合物（范可尼贫血核心复合物和布鲁姆溶解体）的关键界面的小分子来扩大选择性化疗DNA修复靶点的范围。我们已经使用X射线晶体学，生物化学和细胞生物学方法来揭示这一关键性质。 用于细胞基因组稳定性的高阶复合物。在这项提议中，我们将使用高通量化学筛选来鉴定破坏Fanconi贫血核心复合物/Bloom dissolvasome超复合物的蛋白质相互作用抑制剂。经典的生物化学和结构方法将用于评估抑制剂的效力和作用机制，并推动未来合理的铅改进。先导化合物的化学治疗潜力将通过测量它们对由超复合物修复的特定类型的DNA损伤的作用和通过评估它们是否选择性地抑制癌性人类细胞系的生长来确定。

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.