Small Molecule Screen Identifies Non-Catalytic USP3 Chemical Handle-Reference-Cited by-同舟云学术

Small Molecule Screen Identifies Non-Catalytic USP3 Chemical Handle

Published:2023-03-01 Issue: Volume: Page:
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Author:

Mann Mandeep K.,Wolf Esther,Silva Madhushika,Kwak Haejin,Wilson Brian,Wilson Derek J.,Harding Rachel J.,Schapira Matthieu^ORCID

Abstract

ABSTRACTZinc-finger ubiquitin binding domains (ZnF-UBDs) are non-catalytic domains mostly found in deubiquitylases (DUBs). They represent an underexplored opportunity for the development of deubiquitylase-targeting chimeras (DUBTACs) to pharmacologically induce the deubiquitination of target proteins. We have previously shown that ZnF-UBDs are ligandable domains. Here, a focused small molecule library screen against a panel of eleven ZnF-UBDs led to the identification of59, a ligand engaging the ZnF-UBD of USP3 with a KDof 14 µM. The compound binds the expected C-terminal ubiquitin binding pocket of USP3 as shown by hydrogen-deuterium exchange mass spectrometry experiments and does not inhibit the cleavage of K48-linked di-ubiquitin by USP3. As such this compound could serve as a chemical starting point to develop bifunctional DUBTACs recruiting USP3 for targeted deubiquitination.Table of contents graphic

Publisher

Cold Spring Harbor Laboratory

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