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

摘要：几种已建立的癌症治疗方法利用了癌细胞比非癌细胞对化学和放射治疗的DNA损伤更敏感这一事实。然而，这种方法的一个缺点是，不加区分的DNA损伤会对非癌细胞产生毒性作用，这使得直接针对单个DNA修复蛋白的更具体的治疗方法非常有价值。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具选择性的基因组不稳定剂显示出巨大的前景。该提案旨在通过开发小分子来阻断连接两个DNA修复复合物（Fanconi Anemia核心复合物和Bloom溶酶体）的关键界面，从而扩大选择性化疗DNA修复靶点的范围。我们使用了x射线晶体学、生物化学和细胞生物学的方法来揭示这一关键的本质

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.