Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells

Journal article

Immunomodulatory imide drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short degron motif, which often comprises a zinc finger (ZF). These IMiDs, however, also induce the degradation of endogenous ZF-containing neosubstrates, including IKZF1, IKZF3, and SALL4. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogues against 8380 ZF mutants. This yielded a bumped IMiD analogue that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1, IKZF3, and SALL4. In proof-of-concept studies, this system was applied to induce degradation of the optimum degron fused to CDK9, HPRT1, NanoLuc, or TRIM28. We anticipate that this system will be a valuable addition to the current arsenal of degron systems for use in target validation.

Authors: Brennan, PJ; Saunders, RE; Spanou, M; Singleton, SE; Serafini, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Chemical Biology
• Volume: 20
• Issue: 11
• Pages: 2827-2843
• Publication date: 2025-11-02
• Acceptance date: 2025-10-24
• DOI: 10.1021/acschembio.5c00751
• EISSN: 1554-8937
• ISSN: 1554-8929
• Language: English