A Target Class Approach to Deubiquitinase Inhibitor Discovery

Abstract

Deubiquitinases (DUBs) have been proposed as therapeutic targets in cancer due to their ability to alter degradation rates of known oncoproteins. However, previous efforts to develop potent and selective DUB inhibitors have been largely unsuccessful. In this work, we develop a target class drug discovery platform targeting DUBs, which incorporates small molecule libraries, enzyme libraries, and a suite of structural and functional activity assays. Using this platform, we demonstrate one of the first examples of potent and selective DUB inhibitor development, targeting USP7 (chapter II). We then use our potent USP7 inhibitors (chapter III) as well as our annotated DUB-wide small molecule library (chapter IV) in a series of cellular assays to identify novel biological function of USP7 (chapter III) and USP10 (chapter IV). Finally, we describe our efforts to improve and expand our current target class library in order to continue to identify novel DUB inhibitors and DUB biology.