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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端结合蛋白（CtBP） 1和2作为转录共调节因子