Date of Award


Document Type


Degree Name

Philosophy (Ph.D)


Pharmaceutical Sciences

First Advisor

Aaron Dr. Muth

Second Advisor

Vijaya Dr. Korlipara

Third Advisor

Sabesan Dr. Yoganathan


Gankyrin was first identified as an oncoprotein in hepatocellular carcinoma but was later found to be overexpressed in multiple cancer types. Gankyrin’s oncogenic ability is primarily manifested through its interactions with tumor suppressor proteins, regulation of transcription factors, and ability to moderate various signaling pathways. Additionally, gankyrin has been shown to decrease tumor suppressor protein levels (e.g., Rb and p53) in liver cancer cells. Cjoc42 was the first small molecule inhibitor of gakyrin; however, it also demonstrated poor anti-proliferative activity against liver cancer cells. Molecular modeling studies of cjoc42 with gankyrin suggests cjoc42 adopts a U-shape conformation upon binding to gankyrin, which may be contribute for its activity. To assess the importance of this U-shape conformation on anti-proliferative activity and gankyrin binding ability, the propyl linker of the cjovc42 scaffold was replaced with various cyclic and acyclic linkers. These derivatives helped in understanding the impact of cjoc42 conformational flexibility and rigidity on the anti-proliferative activity and gankyrin binding in liver and breast cancer cells. Conformationally constrained derivatives then significantly improved the anti-proliferative activity against HuH6 and MDA-MB-231 cells while also showing an ability to effectively bind gankyrin, disrupt the proteasomal degradation pathway, and cause cell cycle arrest.

Available for download on Thursday, May 22, 2025