Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor. Issue 2 (15th January 2019)

• Record Type: Journal Article
• Authors: Long, Marcus J.C.; Lawson, Ann P.; Baggio, Rick; Qian, Yu; Rozhansky, Lior; Fasci, Domenico; El Oualid, Farid; Weerapana, Eranthie; Hedstrom, Lizbeth
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 2(2019)
• Page Start: 204
• Page End: 211
• Publication Date: 2019-01-15
• Subjects: Activity profiling -- USP7 -- USP9 -- Bcr Abl -- Mdm2; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.11.055
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Deubiquitinating enzymes (DUBs) are drug targets for cancer and other diseases. Diarylcarbonates are a new class of reversible DUB inhibitors. Diarylcarbonates are cell permeable and less toxic than other pan-DUB inhibitors. CompoundC17 inhibits USP7 and USP9x and elicits the expected cellular effects. Abstract: 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.