Date of Award
MS in Chemistry
Philip S Lukeman
Gankyrin is an oncogenic protein directly involved in various biological processes, such as cellular growth, cell cycle progression, cell proliferation, and invasion. Gankyrin overexpression has been observed in many cancer types, and gankyrin either directly or indirectly regulates key biochemical pathways related to cancer progression through its various protein-protein interactions (PPIs). Gankyrin interacts with retinoblastoma protein (pRb), cyclin-dependent kinase 4 (CDK4), mouse double minute2 (MDM2) and the S6 ATPase of the 19S regulatory cap of the 26S proteasome. Each of these PPIs controls the degradation of key tumour suppressor proteins, which in turn controls cell proliferation, migration and metastasis. Overexpression of gankyrin in cancer cells is directly linked to these cellular activities. The first non-peptide-based small inhibitor, cjoc42, was discovered in 2016 and inhibited the binding of gankyrin and the S6 ATPase of the 26S proteasome leading to diminished proliferation in certain cancers. Despite this advance, cjoc42 has 2 major flaws: low binding affinity and poor water solubility. In order to improve on the cjoc42 scaffold and address these issues, a series of heterocycles were introduced to the cjoc42 scaffold. Herein we describe the synthesis and biological evaluation of these next-generation cjoc42-based gankyrin inhibitors.
Juang, Yi-Chih, "SYNTHESIS AND BIOCHEMICAL EVALUATION OF HETEROARYL CJOC42 DERIVATIVES FOR GANKYRIN BINDING" (2020). Theses and Dissertations. 120.