Date of Award

Spring 2020

Degree Type



College of Pharmacy

Director of Thesis

Dr. Michael Wyatt

Second Reader

Dr. Campbell McInnes


Polo-Like Kinase 1 (PLK1) is a protein that has been found to be overexpressed in a variety of cancers including prostate and colorectal cancers, and it is often an indicator of poor patient prognosis. It has functions in initiating, maintaining, and completing mitosis, so it has an important role in controlling the proliferation of cells. PLK1 contains a highly conserved catalytic kinase domain and a less-conserved Polo Box Domain (PBD). Inhibiting the phospho-ligand binding of the PBD is a potential cancer therapy because it would prevent the cell from properly completing the cell cycle, thus inducing apoptosis. In Dr. McInnes’ lab, a partner lab to Dr. Wyatt’s lab, a technique called Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) was used to develop Fragment ligand inhibitory peptides (FLIPs) using the recognition sequences of PLK1 PBD substrates. The FLIPs were used as a guide to develop ABBA ( 2-(4-alkylbenzamido)benzoic acid), a small-molecule inhibitor. This project involved the performance of a structure-activity relationship (SAR) analysis on several ABBA and FLIP molecules with slight chemical alterations to determine the chemical structures that had the highest binding affinity to PLK1 PBD. The molecules were compared using half maximal inhibitory concentrations (IC 50 ), which are the concentrations of inhibitor that bind 50% of the PLK1 PBD in a sample. These values were determined through the performance of a fluorescence polarization (FP) assay. Polo-Like Kinase 3 (PLK3) is a protein in the mammalian PLK family that functions as a tumor suppressor, so the molecules that would have the best potential as guides for anticancer drugs should have high specificity for PLK1 over PLK3. In this project, the IC 50 values of 26 inhibitor molecules were determined to observe which specific chemical alterations increased their affinity and specificity to PLK1 PBD.

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