Work

A Proximity-Driven Functional Screening Platform for the Discovery of Noninhibitory USP7 Ligand Enabling Targeted Protein Stabilization

Year: 2026

Type: preprint

Abstract: Targeted protein stabilization by deubiquitinase-targeting chimeras (DUBTACs) has emerged as a promising therapeutic strategy for preserving the function of essential proteins. DUBTACs are bifunctional molecules that recruit deubiquitinating enzymes (DUBs) to remove ubiquitin chains from substrate proteins, thereby preventing their proteasomal degradation. A key requirement for DUBTACs development is the identification of ligands that bind DUBs without impairing their catalytic activity. However, such noninhibitory ligands are exceedingly rare. Here, we report a novel proximity-driven on-bead functional screening platform for the discovery of noninhibitory DUB ligands. Using this approach, we discovered a previously unreported noninhibitory ligand for USP7. Furthermore, we generated DUBTACs by conjugating this USP7 ligand to a CFTR-binding ligand. Our lead compound, WJ045, effectively stabilized CFTR protein levels in cells, demonstrating the potential of this platform for discovering DUB recruiters and facilitating the development of targeted protein stabilization therapeutics.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.09.10.750156

Authors: Kate E. Young, Janitha Kumarathunga, Hiruni Kandambi, Vitoria Fernandes Ferro, Weijun Gui

Institution: Syracuse University

Language: English

Topic: Protein Degradation and Inhibitors

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: Syracuse University