February 2020.

Ubiquitin-specific proteases (USPs), the major class of deubiquitinating enzymes, or DUBs, remove conjugated ubiquitin from proteins in cells and in so doing help to regulate the content, location, or activity of the target protein. Approximately 80 USPs are expressed in humans, and many are linked genetically and biochemically with various diseases including cancer, cardiovascular disease, neurodegeneration, inflammation and asthma, and metabolic diseases. Pathology-linked USPs have become actively investigated therapeutic targets for the development of new medicines in these and other diseases. Despite all this work, not any DUB based drugs have entered clinical trials, and DUBs are regarded by some as undruggable because their common mechanism of hydrolysis and the active site (a conserved catalytic triad) shared with other cysteine protease classes. Nevertheless, the search for a USP-based drug continues as increasing evidence suggests that potent and highly selective inhibitors of individual DUBs can be developed. This evidence comes primarily from structural studies employing NMR and X-ray crystallography. In addition, the therapeutic utility of irreversible inhibitors is gaining acceptance. Progenra has been engaged in developing DUB inhibitors for several years, and three of the company’s researchers, medicinal chemists Jian Wu and Xu Wang and head of drug discovery Suresh Kumar, recently summarized the state of modulators of various USPs in drug development in a chapter in Medicinal Chemistry Reviews (Volume 54, Chapter 17) entitled Advances in the Development of De-ubiquitinase (DUB) Inhibitors.

Read the Full Chapter in 2019 Medicinal Chemistry Reviews, Volume 54, Chapter 17. Advances in the Development of De-ubiquitinase (DUB) Inhibitors. J. Wu et al.