Examination Date
Spring 3-31-2026
Degree
Dissertation
Degree Program
Human Genetics
Examination Committee
Qiang Shen, Bolin Liu, Jiri Adamec, Samarpan Majumder, Krzysztof Reiss
Abstract
Oridonin-based compounds, including the thiazole-fused analog CYD0618, demonstrate potent anticancer activity in triple-negative breast cancer (TNBC), yet their molecular targets remain undefined. Prior evidence of covalent STAT3 modification by CYD0618 supported STAT3 as a putative direct target. We therefore developed oridonin- and CYD0618-based proteolysis-targeting chimeras (PROTACs) as candidate STAT3 degraders. Lead PROTACs exhibited potent anticancer activity, but STAT3 was systematically excluded as both a primary degradation target and a mechanistic mediator. Moreover, STAT3 was dispensable for apoptosis induced by established STAT3 inhibitors across breast cancer models, suggesting that STAT3 alone may not represent an intrinsic therapeutic vulnerability in some solid tumors. These findings redirected the investigation toward unbiased target identification strategies guided by the cysteine-reactive electrophilic chemistry of the oridonin scaffold. Transcriptomic profiling and computational target landscape analysis revealed that oridonin-based compounds suppress proliferative programs enriched for ligandable, TNBC-dependent genes. Affinity pulldown and degradation-based proteomic profiling were integrated to identify target candidates that are both physically engaged and downregulated by degrader treatment. Prioritization with chemoproteomic and genetic dependency criteria identified 26 high-priority target candidates for future validation. Together, this work demonstrates that STAT3 alone is not a sufficient intrinsic therapeutic target in tested breast cancer models, identifies candidate mediators of oridonin-based anticancer activity, and provides a flexible prioritization framework for future target validation and rational scaffold optimization.
Recommended Citation
Vontz, Gabrielle, "DEFINING MECHANISMS OF ACTION AND TARGET LANDSCAPES OF NOVEL ORIDONIN-BASED AGENTS IN TRIPLE NEGATIVE BREAST CANCER" (2026). School of Graduate Studies. 25.
https://digitalscholar.lsuhsc.edu/etd_sgs/25
Dissertation Report Form