Gankyrin is an ankyrin-repeat oncoprotein involved in various protein-protein interactions (PPIs) resulting in the regulation of numerous oncogenic pathways. Gankyrin is overexpressed in a variety of cancers, such as liver, breast, and lung cancer, as well as others. Therefore, gankyrin has been identified a potential target for the treatment of these cancers. Gankyrin has the capacity to regulate the expression levels of various tumor suppressor proteins by functioning as a proteasomal chaperone. The first small molecule gankyrin inhibitor, cjoc42, was identified in 2016 and demonstrated an ability to inhibit liver cancer proliferation. Molecular modeling studies have indicated the propyl linker of cjoc42 could be modified to enhance both gankyrin binding and subsequently anti-proliferative activity. Therefore, we developed an extensive SAR for this propyl linker by synthesizing a series of cjoc42 derivatives, and then evaluated them for their gankyrin binding ability as well as their ability to inhibit the proliferation of gankyrin overexpressing liver, lung, and breast cancer cell lines. Herein, we report the synthesis and evaluation of these derivatives.

Structural modification of the propyl linker of cjoc42 for enhanced gankyrin binding and anti-cancer activity

ACS Spring 2022

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