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.

Public Health Relevance

The goal of this project is to characterize C-terminal Binding Protein (CtBP) as a therapeutic target. CtBP is a transcriptional co-regulatory protein that has been strongly implicated in many types of cancer by promoting metastasis and inhibiting apoptotic cell death. Our studies are directed at developing inhibitors that could lead to highly selective anti-neoplastic CtBP inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM119014-02
Application #
9455743
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fabian, Miles
Project Start
2017-04-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Bellesis, Andrew G; Jecrois, Anne M; Hayes, Janelle A et al. (2018) Assembly of human C-terminal binding protein (CtBP) into tetramers. J Biol Chem 293:9101-9112