UbiQ is proud to be part of a collaborative project reported in Bioorganic & Medicinal Chemistry Letters (2019, 29, 204), describing a series of diarylcarbonates as promiscuous deubiquitinating enzyme (DUB) inhibitor. In contrast to other promiscuous inhibitors, the reported class of diarylcarbonate inhibitors shows a relatively small off-target spectrum and does not induce insoluble ubiquitin aggregates. To assess the selectivity of DUB inhibition, lysates from HEK 293T cells treated with diarylcarbonates were analyzed by activity profiling with probe UbiQ-187 (HA-Ahx-Ahx-Ub-VS). Overall, the diarylcarbonates serve as valuable research tools for the study of regulatory pathways, stabilizing lysates and as starting points for the design of more selective DUB inhibitors.

Promiscuous inhibitors of tyrosine protein kinases, proteases and phosphatases are useful reagents for probing regulatory pathways and stabilizing lysates as well as starting points for the design of more selective agents. Ubiquitination regulates many critical cellular processes, and promiscuous inhibitors of deubiquitinases (DUBs) would be similarly valuable. The currently available promiscuous DUB inhibitors are highly reactive electrophilic compounds that can crosslink proteins. Herein we introduce diarylcarbonate esters as a novel class of promiscuous DUB inhibitors that do not have the liabilities associated with the previously reported compounds. Diarylcarbonates stabilize the high molecular weight ubiquitin pools in cells and lysates. They also elicit cellular phenotypes associated with DUB inhibition, demonstrating their utility in ubiquitin discovery. Diarylcarbonates may also be a useful scaffold for the development of specific DUB inhibitors.