USP28-Based Deubiquitinase-Targeting Chimeras for Cancer Treatment
Zhen Wang1, Chao Qian2, Yan Xiong2
1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.
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.
Insights
Deubiquitinase-targeting chimeras (DUBTACs) now leverage USP28 to stabilize proteins. This new approach successfully targets mutant CFTR, cGAS, and PPARγ, advancing targeted protein stabilization therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Deubiquitinase-targeting chimeras (DUBTACs) represent a novel therapeutic strategy for stabilizing tumor suppressors.
- Current DUBTAC development has primarily utilized OTUB1 and USP7.
- Targeting protein stabilization offers a new avenue beyond conventional therapeutic approaches.
Purpose of the Study:
- To explore the potential of USP28 as a deubiquitinase (DUB) for DUBTAC development.
- To create and evaluate USP28-recruiting DUBTACs for stabilizing target proteins.
- To investigate the therapeutic potential of novel DUBTACs in cancer metabolism and genetic disorders.
Main Methods:
- Development of USP28-recruiting DUBTACs using a noncovalent USP28 ligand.
- Assessment of DUBTAC efficacy in stabilizing ΔF508-CFTR mutant protein.
- Creation and evaluation of USP28-recruiting cGAS DUBTACs and PPARγ DUBTACs.
Main Results:
- USP28-recruiting DUBTACs demonstrated comparable efficacy to existing OTUB1- and USP7-based DUBTACs in stabilizing ΔF508-CFTR.
- USP28-recruiting cGAS DUBTACs stabilized cGAS, enhanced the cGAS-STING pathway, and produced antiproliferative effects.
- First-in-class PPARγ DUBTACs successfully stabilized PPARγ and inhibited cancer cell proliferation.
Conclusions:
- USP28 is a viable target for developing novel DUBTACs.
- USP28-recruiting DUBTACs show promise for treating conditions involving ΔF508-CFTR, cGAS pathway dysregulation, and cancer metabolism.
- This research expands the utility of DUBTACs for targeted protein stabilization and offers new therapeutic strategies.
