New Functional Screen Identifies Noninhibitory USP7 Ligand Enabling DUBTAC-Based CFTR Stabilization
- Ligands that bind deubiquitinating enzymes (DUBs) without blocking their catalytic activity are notoriously hard to find — a new on-bead, proximity-driven functional screening platform is designed to identify them.
- Such noninhibitory DUB ligands are essential for building DUBTACs (deubiquitinase-targeting chimeras), bifunctional molecules that stabilize target proteins by recruiting DUBs to strip ubiquitin marks, the inverse of degrader-based targeted protein degradation.
- That rarity has made noninhibitory DUB ligands the central bottleneck in DUBTAC development.
- Using the platform, the team discovered a previously unreported noninhibitory ligand for the deubiquitinase USP7.
- Conjugating this USP7 ligand to a CFTR-binding moiety produced a DUBTAC lead, WJ045, which stabilized cellular CFTR protein levels.
- The results demonstrate the platform's utility for discovering DUB-recruiting ligands and advancing targeted protein stabilization, with relevance to cystic fibrosis biology.
A noninhibitory DUB ligand is a harder ask than it sounds - you need a binder that occupies USP7 without touching the catalytic cleft, so a standard activity-inhibition screen is the wrong tool entirely. That's what makes the on-bead, proximity-driven functional assay the real story here: it's a hit-finding method, not just a molecule, and if it generalizes across other DUBs it addresses the actual bottleneck in this space. DUBTACs have quietly been the underdeveloped mirror image of degrader chemistry for years - everyone chasing PROTACs, almost nobody with tractable DUB recruiters in hand. WJ045 stabilizing CFTR is a nice proof point tying this to real biology, though it's a single cellular readout so far - want to see USP-family selectivity and whether the platform yields a second, unrelated ligand.