Structure-based characterization of CtBP as a therapeutic target in cancer

C-末端结合蛋白（CtBP）1和2作为转录辅助调节因子， 调节许多细胞过程，包括涉及基因组稳定性的抑制基因， 上皮分化和凋亡。大量证据表明CtBP在多个人类 癌的CtBP含有功能性酶结构域，提供底物、辅酶和 相邻的口袋，这是非常不寻常的转录因子和潜在的 对缓蚀剂设计有价值。我们对CtBP 1和CtBP 2的晶体学分析显示， 我们已经在基于结构的药物设计中使用了活性位点的独特细节， 开发迄今为止鉴定的最高亲和力的CtBP抑制剂。我们制定了一份 结构生物学、基于结构的药物设计、癌症 生物学和药物化学来扩展这些研究。我们的项目将使用计算 分析结合位点，以识别潜在的抑制剂;将通过以下方法筛选已识别的抑制剂： 酶和生物物理技术，以确定结合亲和力和晶体学分析 以确定结合的立体化学。这些结果将为新的化学合成提供信息 来开发更多的抑制剂我们还将研究低聚和催化的作用 在CtBP的转录功能，以通知其他抑制剂的设计和合成研究。 这些研究旨在了解CtBP的结构和功能， 涉及在癌症中CtBP的研究中可用作重要分子探针的抑制剂， 最终，发展高选择性抗肿瘤CtBP抑制剂。

C-terminal Binding Proteins (CtBP) 1 and 2 operate as transcriptional coregulators that modulate numerous cellular processes including repressing genes involved in genome stability, epithelial differentiation and apoptosis. Substantial evidence implicates CtBP in multiple human cancers. CtBP contains a functional enzymatic domain, providing substrate, coenzyme and adjacent pockets, which is both highly unusual among transcription factors and potentially valuable for inhibitor design. Our crystallographic analysis of CtBP1 and CtBP2 has revealed unique details of the active site that we have already used in structure based drug design to develop the highest affinity CtBP inhibitor identified to date. We have assembled an interdisciplinary team with strengths structural biology, structure based drug design, cancer biology and medicinal chemistry to extend these studies. Our project will use computational analysis of the binding sites to identify potential inhibitors; those identified will be screened by enzymatic and biophysical techniques to determine binding affinity and crystallographic analysis to determine the stereochemistry of binding. These results will inform novel chemical synthesis to develop additional inhibitors. We will also investigate the role of oligomerization and catalysis in CtBP transcriptional function to inform additional inhibitor design and synthesis studies. These studies are directed at understanding CtBP structure and function at a level that will lead to inhibitors that can serve as important molecular probes in the study of CtBP in cancer and, eventually, to the development of highly selective anti-neoplastic CtBP inhibitors.