ORCID

https://orcid.org/0000-0001-6541-6494

Date of Award

2022

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Aaron Muth

Second Advisor

Carlos Chavez

Third Advisor

Tanaji Talele

Abstract

Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer, however, gankyrin’s regulation of TSPs in breast and lung cancer has not been thoroughly investigated. Additionally, no small molecule gankyrin inhibitor has been developed which demonstrates potent antiproliferative activity against gankyrin overexpressing breast and lung cancers. Therefore, two different scaffolds were utilized to develop potent gankyrin binding small molecules. First, derivatives of the cjoc42 scaffold were developed with improved metabolic stability, gankyrin binding, and anti proliferative activity against A549 and MDA-MB-231 cells, while also demonstrating an ability to disrupt the proteasomal degradation pathway mediated by gankyrin. Second, an HTVS screen produced a novel gankyrin binding scaffold which was then derivatized producing analogs with improved antiproliferative activity and gankyrin binding. Optimization of two scaffolds also provided the requisite tools to shed light on how gankyrin regulates proliferation while also demonstrating that gankyrin is a viable therapeutic target for the treatment of breast and lung cancer.

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