By investigating the structure–activity relationship of molecular glue degraders that target cyclin K, we discovered that a wide range of compounds, including known kinase inhibitors, possess this gain-of-function activity. These findings provide insights that might enable more rational design and optimization of molecular glue compounds.
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Change history
14 September 2023
In the version of this article initially published, “IMiDs” (immunomodulatory imide drugs) was written more generally as “immunomodulatory drugs”; the text has been updated in the HTML and PDF versions of the article.
References
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Leissing, T. M., Luh, L. M. & Cromm, P. M. Structure driven compound optimization in target protein degradation. Drug Discov. Today Technol. 37, 73–82 (2020). A review article that provides an overview of structurally characterized degrader-mediated complexes.
Słabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020). This paper reports the discovery of the first cyclin K degrader CR8 and its ternary complex structure.
Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020). This paper reports the discovery of structurally distinct cyclin K degraders by differential compound profiling in hyponeddylated versus wild-type cellular models.
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This is a summary of: Kozicka, Z. et al. Design principles for cyclin K molecular glue degraders. Nat. Chem. Biol. https://doi.org/10.1038/s41589-023-01409-z (2023).
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Unraveling the diversity of molecular glue degraders. Nat Chem Biol 20, 17–18 (2024). https://doi.org/10.1038/s41589-023-01410-6
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DOI: https://doi.org/10.1038/s41589-023-01410-6
