The p97 AAA ATPase is an active regulator of protein homeostasis, influencing protein degradation and translocation. Dysregulated p97 is adversely associated in aging, cancer, and neurodegeneration; therefore, p97 is an emerging biological target for therapeutic development. Our pursuit toward a p97 small molecule modulator led to the elaboration and optimization of a series of allosteric inhibitors that perturb p97 ATPase activity. These compounds were robustly constructed from an advanced intermediate with a common heterocyclic core, employing a convergent synthetic strategy of thioalkylations, Williamson etherifications, Sonogashira couplings, and carbamoylations, which efficiently provided final products in high overall yields. The established medicinal chemistry discovery routes enabled rapid derivation of analogs that were strategically designed to enhance biological properties.

Modular synthesis of allosteric inhibitors of p97 AAA ATPase

256th National Meeting (2018)

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