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发挥作用 调节许多细胞过程，包括抑制与基因组稳定有关的基因， 上皮分化与细胞凋亡。大量证据表明CtBP与多名人类有关 癌症。CTBP含有一个功能性的酶结构域，提供底物、辅酶和 相邻的口袋，这在转录因子中非常不寻常，而且可能 对缓蚀剂的设计有一定的参考价值。我们对CtBP1和CtBP2的晶体分析揭示了 我们已经在基于结构的药物设计中使用的活性部位的独特细节 开发迄今发现的亲和力最高的CtBP抑制剂。我们已经组装了一个 跨学科团队，擅长结构生物学、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 分析结合部位以确定潜在的抑制剂；已确定的将通过以下方式进行筛选 测定结合亲和力和结晶学分析的酶和生物物理技术 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。 以开发更多的抑制剂。我们还将研究齐聚和催化的作用。 在CtBP转录功能中，为更多的抑制剂设计和合成研究提供信息。 这些研究旨在了解CtBP的结构和功能，从而在一个水平上 在癌症和CtBP的研究中可以作为重要的分子探针的抑制剂， 最终，发展高选择性的抗肿瘤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.