Diarylcarbonates are a new class of deubiquitinating enzyme inhibitor

Bioorg Med Chem Lett. 2019 Jan 15;29(2):204-211. doi: 10.1016/j.bmcl.2018.11.055. Epub 2018 Nov 28.

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.

Keywords: Activity profiling; Bcr Abl; Mdm2; USP7; USP9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonates / chemical synthesis
  • Carbonates / chemistry
  • Carbonates / pharmacology*
  • Deubiquitinating Enzymes / antagonists & inhibitors*
  • Deubiquitinating Enzymes / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship
  • Ubiquitination / drug effects

Substances

  • Carbonates
  • Enzyme Inhibitors
  • Deubiquitinating Enzymes