ACS chemical biology · 2025
Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Brennan Patrick J, Saunders Rebecca E, Spanou Mary, Singleton Sarah E, Serafini Marta, Sun Liang, Heger Guillaume P, Konopacka Agnieszka, Beveridge Ryan D, Taylor C Cameron, DePaola Peter, Gordon Laurie, Bunally Shenaz B, Saudemont Aurore, Benowitz Andrew B, Martinez-Fleites Carlos, Schmitt Danielle L, Damoiseaux Robert, Queisser Markus A, An Heeseon, Deane Charlotte M, Hann Michael M, Brayshaw Lewis L, Conway Stuart J
Аннотация
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.