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

基本信息

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
项目类别：
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

项目摘要

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末端结合蛋白（CTBP）1和2作为转录核心调节剂，调节许多细胞过程，包括抑制基因组稳定性的基因，上皮分化和凋亡。大量证据暗示了多个人类的CTBP 癌症。 CTBP包含一个功能性酶结构域，可提供底物，辅酶和邻近的口袋，在转录因子中既高度不寻常，又可能对于抑制剂设计很有价值。我们对CTBP1和CTBP2的晶体学分析已显示我们已经在基于结构的药物设计中使用的主动站点的独特细节开发迄今为止确定的最高亲和力CTBP抑制剂。我们已经组装了跨学科团队具有优势结构生物学，基于结构的药物设计，癌症生物学和药物化学以扩展这些研究。我们的项目将使用计算分析结合位点以鉴定潜在的抑制剂；确定的那些将由酶促和生物物理技术以确定结合亲和力和晶体学分析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。我们还将研究寡聚和催化的作用在CTBP转录函数中，为其他抑制剂设计和合成研究提供了信息。这些研究旨在理解CTBP的结构和功能，以领导在癌症中CTBP研究中可以作为重要分子探针的抑制剂和最终，发展高度选择性的抗塑性CTBP抑制剂。