Author ORCID Identifier
0000-0002-7838-7116
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Yan Zhang
Abstract
Despite advances in cancer therapy, late-stage tumors frequently develop resistance and relapse, driven by cancer stem cells (CSCs). FOSL1 is overexpressed in CSCs and promotes invasion, survival, and chemoresistance; yet no FOSL1 inhibitor has entered the clinic. T-5224 suppresses HNSCC tumor growth and metastasis, but its limited potency restricts its utility. In the first project, we used a deconstruction-reconstruction-elaboration approach to design T-5224 11 analogs, identifying four that bind the FOSL1/JUN heterodimer. The benzoisoxazole is required for interaction, whereas the benzophenone is key for binding-site occupancy. Among the analogs, compound 3 downregulated FOSL1, inhibited HNSCC cell proliferation ~tenfold more than T-5224, and reduced migration and CSC-sphere formation. It suppressed tumor growth at 50 mg/kg, comparable to T-5224, with no significant weight loss in xenograft mouse models.
PROTACs have been shown to eliminate CSCs and suppress HNSCC growth. In the second project, CRBN and VHL E3 ligase ligands with different PEG linker lengths were synthesized using T-5224. Binding studies showed that each E3 ligase required a distinct optimal linker length, necessitating empirical optimization. In the CRBN series, shorter linkers showed stronger binding; however, VZPT059, with a linker length (n=7), achieved the strongest degradation (DC50 ~0.4 µM; Dmax 99%) compared to VZPT052. VHL PROTACs with PEG5 or PEG6 linkers also degraded effectively. They inhibited proliferation, migration, and stem-cell sphere formation, showing 8–10-fold selectivity. In a mouse model, VZPT059 suppressed tumors and depleted active FOSL. Overall, targeting FOSL1 effectively addressed both the tumor and resistant stem cells that drive resistance and recurrence.
Rights
© Sarita Pandit
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-3-2026