USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment.

Deubiquitinase-targeting chimeras (DUBTACs) are an emerging class of therapeutics that can stabilize tumor suppressors by hijacking a deubiquitinase (DUB), thereby offering a strategic pivot from conventional approaches to target tumor suppressors. However, only OTUB1 and USP7 have been harnessed for DUBTAC development to date. Here, we show for the first time that USP28 can be leveraged for developing DUBTACs. Utilizing a USP28 noncovalent ligand, we crafted USP28-recruiting DUBTACs that effectively stabilized the ΔF508-CFTR mutant protein, with comparable effectiveness to the previously reported OTUB1- and USP7-recruiting CFTR DUBTACs. Furthermore, we developed USP28-recruiting cGAS DUBTACs that effectively stabilized cGAS, elevated the cGAS-STING signaling pathway, and elicited an antiproliferative effect. We also developed first-in-class PPARγ DUBTACs to target cancer metabolism pathways. Our lead PPARγ DUBTACs effectively stabilized PPARγ and suppressed cancer cell proliferation, thus providing a new potential anticancer therapeutic approach. Hence, this work advances the targeted protein stabilization field.