Deubiquitinase inhibitors: from evolving concepts to preclinical evaluation

Deubiquitinases (DUBs) regulate substrate ubiquitination, thereby modulating signal transduction, trafficking, and proteasomal degradation. They have emerged as promising therapeutic targets owing to their involvement in a variety of pathological conditions. However, the limited availability of DUB inhibitors with adequate specificity, safety, and efficacy remains a major barrier to successful clinical translation. Recent studies indicate that exploring both allosteric and covalent inhibition strategies together with integrated computational workflows could address this gap. In this review, we summarize current developments concerning the chemistry of small-molecule DUB inhibitors, improved computational discovery workflows, and the preclinical evaluation of candidate compounds.