Organic Colloquium
University of Pennsylvania
Department of Chemistry
Description
Title: Development of Allosteric Inhibitors of VCP/ p97 to Interrogate Novel Biology and Fuel Cancer Drug Discovery
Abstract: Clinical success in targeting the protein degradation pathway using proteasome inhibitors has spurred efforts to evaluate other aspects of this system as approaches to cancer therapy. Among those, the AAA ATPase, p97/ VCP, a master regulator of protein homeostasis, has recently emerged as a promising target. While there is pre-clinical validation that inhibition of p97 will have anti-tumor effects, a number of key questions still remain about its potential as a target for therapeutic efficacy, as well as its fundamental biology. Through the auspices of the National Cancer Institute’s (NCI’s) Chemical Biology Consortium, we developed multiple series of novel, potent allosteric inhibitors of p97. We solved the first high-resolution structure of p97 bound to an inhibitor using cryo-electron microscopy, and are using our molecules to decipher the complex biology of p97 and to develop new experimental therapeutics.
