Gankyrin is a key and under-investigated protein which regulates numerous cell growth and proliferative pathways through its various protein-protein interactions. The overexpression of gankyrin has been observed in a variety of cancers and appears to mediate their growth and proliferation. In 2016, the first small-molecule binder of gankyrin, cjoc42, was developed and demonstrated an ability to inhibit the proliferation of gankyrin-overexpressing cancer cells by disrupting the gankyrin-26S proteasome interaction and normalizing levels of multiple tumor suppressor proteins. Furthermore, this inhibitor has shown promise for developing a novel class of anti-cancer therapeutics. Therefore, extensive structure-activity relationships were developed for a series of cjoc42 derivatives in an effort to identify key features for developing high affinity binders of gankyrin which also inhibit its interaction with the 26S proteasome. This resulted in a ~5-fold improvement in gankyrin binding, as compared to cjoc42. These 2<sup>nd</sup> generation inhibitors also displayed a substantial improvement in anti-proliferative activity against Hep3B and HepG2 cells as compared to cjoc42.

Optimizing the aryl substitutions of cjoc42 for enhanced gankyrin binding and anti-cancer activity

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.