Small Molecule Screen Identifies Non-Catalytic USP3 Chemical Handle

ABSTRACT

Zinc-finger ubiquitin binding domains (ZnF-UBDs) are non-catalytic domains mostly found in deubiquitinases (DUBs). They represent an underexplored opportunity for the development of deubiquitinase-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 of 59, a ligand selective for USP3 ZnF-UBD that does not inhibit USP3 catalytic activity. A preliminary structure activity relationship of the chemical series informs future development of molecules targeting the USP3 ZnF-UBD domain. The work reported here can be used to further explore the function of the USP3 ZnF-UBD and to develop bifunctional DUBTACs recruiting USP3 for targeted deubiquitination.