Exploiting protein homeostasis for cancer therapy

Cancer cells often harbor numerous genomic insults and an altered metab. Together, these changes impede protein folding and assembly. As a result, cancer cells can have an elevated dependence on mechanisms that sustain protein assembly and quality control. To test whether cancer cells are hypersensitive to inhibition of protein homeostasis pathways, we seek to develop small mol. antagonists of ubiquitin system enzymes involved in protein quality control. In particular, we have been pursuing the proteasome, the COP9-Signalosome, and the ubiquitin-selective 'segregase' p97/VCP. Over the past 5 years we have carried out HTS against these targets through the NIH's Mol. Libraries Program. Anal. of structure-activity relationships for the resulting hits has led to enzyme inhibitors with IC50 ∼0.1-1 μM that are active in cells. These compds. are useful tools for basic research and represent starting points for drug discovery. My talk will focus on our recent progress in developing novel small mol. probes for UPS enzymes