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

基于结构的 CtBP 表征作为癌症治疗靶点

• 批准号: 9308573
• 负责人: WILLIAM E ROYER
• 金额: $ 33.41万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308573
• 关键词: Acids; Active Sites; Address; Affinity; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Binding Sites; Biological Assay; C-Terminal Binding Protein 1; C-terminal binding protein; Calorimetry; Cancer Biology; Catalysis; Cell Culture Techniques; Cell Death; Cell physiology; Coenzymes; Computer Analysis; Computer Simulation; Crystallization; Data; Development; Dimerization; Drug Design; Engineering; Epithelial; Foundations; Genes; Genetic Transcription; Genome Stability; Goals; Histones; Human; Individual; Lead; Malignant Neoplasms; Molecular Probes; Mus; Neoplasm Metastasis; Oxidoreductase; Pharmaceutical Chemistry; Physiological; Probability; Property; Protein Inhibition; Proteins; Publishing; Recruitment Activity; Research; Role; Specificity; Structure; Testing; Therapeutic; Tumor Burden; Variant; base; biophysical techniques; cancer cell; cancer type; chemical synthesis; design; dimer; genetic regulatory protein; inhibitor/antagonist; light scattering; mutant; novel; novel therapeutics; promoter; protein function; protein structure; response; scaffold; screening; small molecule inhibitor; small molecule libraries; stereochemistry; structural biology; therapeutic target; transcription factor

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.

C 端结合蛋白 (CtBP) 1 和 2 作为转录共调节因子， 调节许多细胞过程，包括抑制与基因组稳定性有关的基因， 上皮细胞分化和凋亡。大量证据表明 CtBP 与多种人类有关 癌症。 CtBP 包含功能性酶结构域，提供底物、辅酶和 相邻的口袋，这在转录因子中非常不寻常，并且可能 对抑制剂设计有价值。我们对 CtBP1 和 CtBP2 的晶体学分析表明 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 开发迄今为止发现的亲和力最高的 CtBP 抑制剂。我们组装了一个 具有结构生物学、基于结构的药物设计、癌症优势的跨学科团队 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 分析结合位点以确定潜在的抑制剂；那些被确定的人将被筛选 用于确定结合亲和力和晶体分析的酶促和生物物理技术 以确定结合的立体化学。这些结果将为新型化学合成提供信息 开发额外的抑制剂。我们还将研究低聚和催化的作用 CtBP 转录功能，为其他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，以便在一定程度上引导 抑制剂可作为癌症 CtBP 研究中重要的分子探针， 最终，开发出高选择性抗肿瘤 CtBP 抑制剂。