Date of Award
Spring 2026
Document Type
Open Access Dissertation
Department
College of Pharmacy
First Advisor
Michael Wyatt
Second Advisor
Campbell McInnes
Abstract
Polo-like kinase 1 (PLK1) is a central regulator of mitotic progression whose activity and localization are controlled through coordinated interactions between its catalytic kinase domain (KD) and C-terminal polo-box domain (PBD). PLK1 is frequently overexpressed in cancer and has therefore emerged as an attractive therapeutic target. While most drug discovery efforts have focused on ATP-competitive inhibition of the kinase domain, increasing evidence suggests that small molecules may also regulate PLK1 conformation, stability, and intracellular behavior. However, the mechanistic relationship between inhibitor binding site and PLK1 structural regulation remains incompletely understood.
This dissertation research project investigates the mechanistic and therapeutic consequences of targeting the PLK1 PBD using a novel class of non-peptidic inhibitors termed abbapolins. Structural and biochemical analyses demonstrate reciprocal allosteric communication between the kinase domain and polo-box domain of PLK1, indicating that ligand binding to one domain can influence accessibility of the other. These findings highlight conformational changes as an important mechanistic dimension of PLK1 inhibition and provide a framework for understanding how different inhibitor classes influence PLK1 function.
Translational studies further demonstrate that abbapolins exhibit potent antiproliferative activity in prostate cancer models. Structure–activity relationship optimization identified analogs with improved activity, and in vivo evaluation in prostate cancer xenografts demonstrated significant tumor growth inhibition associated with reduced PLK1 levels in tumors. Extension of these studies to neuroblastoma revealed that abbapolin treatment suppresses tumor cell proliferation and enhances cytotoxic responses when combined with the PARP inhibitor olaparib.
Together, these findings establish abbapolins as mechanistically distinct PLK1 inhibitors capable of modulating protein conformation and stability while exhibiting promising antitumor activity. More broadly, this work highlights the therapeutic potential of targeting regulatory domains which control kinase signaling and provides a conceptual framework for the development of next-generation PLK1-directed therapies.
Rights
© 2026, George Salim Merhej
Recommended Citation
Merhej, G. S.(2026). Abbapolin PLK1 Inhibitors: Potential Cancer Therapeutics and Probes of PLK1 Conformation. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/8750