USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment

  • J Am Chem Soc. 2025 Apr 23;147(16):13754-13763. doi: 10.1021/jacs.5c01889.
Zhen Wang  1 ,  Chao Qian  2 ,  Yan Xiong  2 ,  Dingpeng Zhang  1 ,  Hiroyuki Inuzuka  1 ,  Yue Zhong  2 ,  Ling Xie  3 ,  Xian Chen  3 ,  Jian Jin  2 ,  Wenyi Wei  1
Affiliations
  • 1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
  • 2. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 40214647 DOI: 10.1021/jacs.5c01889
Abstract

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.