Date of Award

Fall 2022

Document Type

Open Access Dissertation

Department

College of Pharmacy

First Advisor

Campbell McInnes

Abstract

PLK1 overexpression has shown to be associated with tumor progression and an unfavorable prognosis in a wide variety of cancer types. Interfering with PLK1 genetically and chemically induces apoptotic cell death in cancer cells thus confirming PLK1 as a validated anticancer target. From a drug discovery perspective, PLK1 offers two functionally distinct, essential, and interconnected target sites in one molecule. These are the ATP binding kinase domain (KD) and the unique Polo Box Domain (PBD), where the interplay between these results in dynamic structural regulation of catalytic activity and sub cellular localization. Since the KD is conserved among kinases and is very similar between the PLK family members (PLK3 has been reported as a tumor suppressor), inhibitors targeting the ATP binding site may have limited applications due to lack of specificity and dose limiting toxicities observed in compounds clinically evaluated. Targeting protein-protein interactions (PPIs) through PBD on the other hand has greater potential for selectivity, even among PLK family members. PBD inhibitors could thus serve as useful chemical biology probes to better understand PBD dependent functions and how PLK1 is regulated. Furthermore, they could be beneficial in developing new therapeutics for PLK1 overexpressing cancers. Development of low molecular weight PPI inhibitors of PLK1 PBD is challenging, but through the application of a systematic structure-based drug design strategy called REPLACE (Replacement with Partial Ligand Alternatives through Computational Enrichment) to the minimal phosphopeptide that can bind to PBD and inhibit PLK1, McInnes lab has developed a library of peptidomimetics called Fragment Ligated Inhibitory Peptides (FLIPs) that possess drug like properties and are selective inhibitors of PLK1 in cells. Further application of REPLACE to these intermediate compounds led to development of non-peptidic compounds termed abbapolins. In-vitro and cellular studies using prostate cancer and neuroblastoma cells show that these inhibitors can selectively bind and inhibit PLK1 by inducing its degradation in a proteasome dependent manner. Lead abbapolins exhibited promising pharmacokinetic properties when administered orally and showed preliminary evidence of anti-tumor activity in in vivo xenograft models of prostate cancer (PC3 and 22rv1(CRPC)), and thus provide proof of concept for development of orally bioavailable PBD inhibitors through structure-based drug design.

Available for download on Sunday, December 15, 2024

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