“DUBs: Therapeutic challenges and opportunities”

Ubiquitin is covalently linked to many cellular proteins to regulate their activities, stability, localisation or interactions. Ubiquitylation is a reversible process carried out by ubiquitin ligases and by deubiquitylating enzymes (DUBs). The human genome encodes approximately 100 DUBs, while additional DUBs are found in many organisms, including viruses and bacteria. Out of the 5 families of DUB enzymes, four (USP, UCH, MJD and OTU) belong to the cysteine peptidases, while one (the JAMM family) belongs to the metallo-peptidases. DUBs have been shown to play critical roles in many pathological processes, particularly cancer, infective diseases and neuro-degeneration, and have thus begun to attract much attention from the pharmaceutical industry. This presentation will describe past challenges faced by the industry in targeting DUBs as well as emerging opportunities in developing drug discovery cascades to overcome inherent thiol protease liabilities and, more specifically, to yield small-molecule drugs targeting DUBs. MISSION Therapeutics’ efforts at targeting DUBs involved in the DNA-damage response will be used to illustrate the challenges and opportunities.

Xavier Jacq

Head of Biology

MISSION Therapeutics Ltd, Cambridge, UK