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.

A video from William Rigby, posted on Aug 29, 2024.

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Following over two decades of clinical success for anti-TNF drugs, antagonists against multiple TNF/TNFR superfamily proteins are in development for IMIDs.

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Symptoms of immune-mediated diseases (IMIDs) typically appear after irreversible tissue damage, making early interventions based on pre-symptomatic indicators crucial. Current efforts to identify mole...

Following over two decades of clinical success for anti-TNF drugs, antagonists against multiple TNF/TNFR superfamily proteins are in development for IMIDs.

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 oft...