Advances in Discovering Deubiquitinating Enzyme (DUB) Inhibitors.

Schauer, Nathan; Magin, Robert S; Liu, Xiaoxi; Doherty, Laura; Buhrlage, Sara

Deubiquitinating enzymes, or DUBs, comprise a family of proteases that regulate ubiquitination dynamics. Since their discovery in the 1980s, genetic and functional studies have nominated DUBs as a promising class for drug discovery across diverse therapeutic areas. Consequent probe and drug discovery efforts over the last 15 years have resulted in more thanover 50 reported inhibitors and advances in DUB structural studies, assay formats, and chemical biology tools. Accumulating knowledge from these studies has enabled increasingly rapid progress in the field, and several important recent breakthroughs have occurred in the past few years. In this review, we highlight recent successes in solving DUB-ligand co-structures and the development of rigorously characterized potent and selective inhibitors. We posit that these advances in pharmacological targeting of DUBs establish the enzyme family as targetable and provide a framework for other DUBs programs. Accordingly, we envision increasingly rapid progress in the development of potent and selective inhibitors for a wide range of DUBs and advancement of DUB-targeting drugs to the clinic.