ORCID

https://orcid.org/0009-0007-9524-7514

Date of Award

2025

Document Type

Dissertation

Degree Name

Pharmaceutical Sciences (Ph.D.)

Department

Pharmaceutical Sciences

First Advisor

Aaron Muth

Second Advisor

Jeanette Perron

Third Advisor

Vijaya Korlipara

Abstract

Gankyrin is an ankyrin-repeat protein overexpressed in certain cancers and is responsible for cell growth and proliferation. Gankyrin is important to the development of many types of cancer, including breast, lung, and liver cancer. Consequently, gankyrin and its various protein-protein interactions, are prospective therapeutic targets for inhibiting the progression of certain cancers. In 2016, the first small molecule inhibitor of gankyrin, cjoc42, was discovered and subsequently demonstrated modest antiproliferative activity against liver cancer cells. Previous work from our lab demonstrated that replacing the sulfonate ester of cjoc42 with an amide group significantly improved gankyrin binding while enhancing antiproliferative activity against lung and breast cancer. Therefore, we have synthesized a series of amide-based cjoc42 derivatives which explored substitutions on the phenyl ring attached to the amide group. These phenyl substitutions were aimed at further improving gankyrin binding and subsequently enhancing antiproliferative activity. Preliminary results have shown a 100-fold improvement in antiproliferative activity against MCF7 cells (breast cancer) compared to cjoc42. Herein, we describe the synthesis and biological evaluation of these cjoc42 derivatives, which will ultimately determine their therapeutic utility and ability to bind gankyrin.

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