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

描述(申请人提供)：摘要：几种成熟的癌症治疗方法利用了这样一个事实，即癌细胞对化学和放射治疗造成的DNA损伤往往比非癌症细胞更敏感。然而，这种方法的一个缺点是，不分青红皂白的DNA损伤可能会对非癌细胞产生毒性影响，这使得直接针对单个DNA修复蛋白的更具体的治疗方法具有很高的价值。最近，阻断DNA修复蛋白多聚ADP核糖聚合酶活性的化疗药物作为更具选择性的基因组失稳剂显示出巨大的前景。这项建议寻求通过开发小分子来阻断连接两个DNA修复复合体-Fanconi贫血核心复合体和Bloom溶解酶复合体-的关键界面，从而扩大选择性化疗DNA修复靶点的范围。我们已经使用了X射线结晶学、生化和细胞生物学方法来揭示这一关键性质 细胞基因组稳定性的高阶复合体。在这项提案中，我们将使用高通量化学筛选来确定破坏Fanconi贫血核心复合体/Bloom溶酶体超复合体的蛋白质相互作用抑制剂。经典的生化和结构方法将被用来评估抑制剂的效力和作用机制，并推动未来合理的铅改善。先导化合物的化疗潜力将通过测量它们对超复合体修复的特定类型的DNA损伤的影响，以及通过评估它们是否选择性地抑制人类癌细胞株的生长来确定。

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.