DOI
https://doi.org/10.25772/GZEF-6N39
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Keith Ellis
Abstract
Many of the most aggressive solid tumor cancers such as breast, ovarian, pancreatic, and colon cancers rely on C-terminal Binding Proteins (CtBPs) for growth and metastasis. CtBP is a transcriptional coregulator that links chromatin remodeling proteins with DNA-bound transcription factors for multiple genes. CtBP overexpression in tumor cells is oncogenic, turning on known oncogenes (e.g., MDR1 and Tiam1) and turning off tumor-suppressor genes (e.g., Bik, PTEN, BRCA1, and E-cadherin). The knockout of CtBP in a mouse xenograft model prevents tumor growth and metastasis, demonstrating its relevance as a therapeutic target. Our lab has developed a long-term program to develop small molecules that inhibit the transcriptional coregulator activity of CtBP to develop new cancer therapeutics. Previous generation CtBP inhibitors, HIPP and JW-43 respectively, have demonstrated the ability to reverse CtBP-mediated oncogenic activity and induce cell death in multiple cancer cell lines and in vivo mouse models. The optimization of HIPP to the more potent JW-43 by modification of the aryl system suggests a promising direction for additional investigations of structure-activity relationships (SAR). To probe the SAR for the naphthyl ring system, three virtual libraries of analogues were designed in sequence based on the structure of JW-43 and the molecular interactions in the CtBP-HIPP co-crystal structure (4U6Q). The libraries of virtual analogues were docked in GOLD and AutoDock Vina and scored with their respective scoring functions. A total of ten high scoring compounds were synthesized and tested in cell viability assays in multiple ovarian cancer cell lines. All analogues performed better than previous CtBP inhibitors, but the NAS-2-133 analogue performed the best, with a single-digit micromolar GI50 in OVCAR4 (GI50 = 3.9 mM) and OVCAR8 (GI50 = 5.4 mM). The mechanism of cell death for NAS-2-133 was found to be apoptosis, and it showed ~10-fold selectivity for ovarian cancer cell line (OVCAR4) over healthy cells (FT-282). In a xenograft mouse model, both NAS-2-133 and NAS-2-134 analogues decreased tumor volume and weight without compromising overall mouse weight over the course of five weeks. This structure-activity relationship study has yielded our most potent and selective CtBP inhibitors to date. These next-generation CtBP inhibitors show genuine potential in becoming a new tumor-selective targeted therapy for ovarian cancer.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-9-2025