Synthesis and evaluation of tiaprofenic acid-derived UCHL5 deubiquitinase inhibitors

Bioorg Med Chem. 2021 Jan 15:30:115931. doi: 10.1016/j.bmc.2020.115931. Epub 2020 Dec 9.

Abstract

The ubiquitin-proteasome system (UPS) plays an important role in maintaining protein homeostasis by degrading intracellular proteins. In the proteasome, poly-ubiquitinated proteins are deubiquitinated by three deubiquitinases (DUBs) associated with 19S regulatory particle before degradation via 20S core particle. Ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) is one of three proteasome-associated DUBs that control the fate of ubiquitinated substrates implicated in cancer survival and progression. In this study, we have performed virtual screening of an FDA approved drug library with UCHL5 and discovered tiaprofenic acid (TA) as a potential binder. With molecular docking analysis and in-vitro DUB assay, we have designed, synthesized, and evaluated a series of TA derivatives for inhibition of UCHL5 activity. We demonstrate that one TA derivative, TAB2, acts as an inhibitor of UCHL5.

Keywords: Deubiquitinase; Proteasome; Tiaprofenic acid; UCHL5 inhibitor.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Propionates / chemical synthesis
  • Propionates / chemistry
  • Propionates / pharmacology*
  • Structure-Activity Relationship
  • Ubiquitin Thiolesterase / antagonists & inhibitors*
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Enzyme Inhibitors
  • Propionates
  • tiaprofenic acid
  • UCHL5 protein, human
  • Ubiquitin Thiolesterase