Exploiting protein homeostasis for cancer therapy

Abstract

Cancer cells often harbor numerous genomic insults and an altered metabolism. 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 molecule 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 Molecular Libraries Program. Analysis 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 compounds 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 molecule probes for UPS enzymes.

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