Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells
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
- Stuart J. Conway (ORCID: https://orcid.org/0000-0002-5148-117X)
- Liang Sun (ORCID: https://orcid.org/0000-0002-0080-0855)
- Laurie Gordon
- Charlotte M. Deane (ORCID: https://orcid.org/0000-0003-1388-2252)
- Guillaume Heger (ORCID: https://orcid.org/0000-0003-4175-133X)
- C. Martinez-Fleites
- Danielle L. Schmitt (ORCID: https://orcid.org/0000-0002-7343-2125)
- Peter DePaola (ORCID: https://orcid.org/0000-0003-4264-0375)
- Ryan Beveridge (ORCID: https://orcid.org/0000-0001-8116-9390)
- Robert D. Damoiseaux (ORCID: https://orcid.org/0000-0002-7611-7534)
- Agnieszka Konopacka (ORCID: https://orcid.org/0000-0003-2192-1928)
- Heeseon An (ORCID: https://orcid.org/0000-0002-8518-4077)
- Aurore Saudemont (ORCID: https://orcid.org/0000-0002-9376-8339)
- Lewis L. Brayshaw (ORCID: https://orcid.org/0000-0003-2696-736X)
- Michael M. Hann (ORCID: https://orcid.org/0000-0003-4360-9505)
- M. Teresa Serafini (ORCID: https://orcid.org/0000-0002-5305-8359)
- Markus A. Queisser (ORCID: https://orcid.org/0000-0002-3368-3827)
- Andrew B. Benowitz (ORCID: https://orcid.org/0000-0002-9913-605X)
- Shenaz B. Bunally
- Mary Spanou
- Rebecca E. Saunders
- Patrick J. Brennan (ORCID: https://orcid.org/0009-0008-8737-9370)
- C. Richard Taylor
- Sarah E. Singleton (ORCID: https://orcid.org/0009-0001-6615-8906)
Institutions
- QB3 (US)
- Memorial Sloan Kettering Cancer Center (US)
- California NanoSystems Institute (US)
- University of California, Los Angeles (US)
- Age UK (GB)
- University of Oxford (GB)
- Institute of Molecular Biology (BG)
- Quantitative BioSciences (US)
- PerkinElmer (United Kingdom) (GB)
- GlaxoSmithKline (Croatia) (HR)
- MRC Weatherall Institute of Molecular Medicine (GB)
- PerkinElmer (United States) (US)
- UCLA Jonsson Comprehensive Cancer Center
Publication Details
- Journal
- ACS Chemical Biology
- Published
- 2025-11-02
- DOI
- https://doi.org/10.1021/acschembio.5c00751
- Citations
- 1
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.81