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Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.

RSC chemical biology

Authors: Pompom Ghosh, Maximilian Schmitz, Thiyagamurthy Pandurangan, Solomon Tadesse Zeleke, Sean Chin Chan, John Mosior, Luxin Sun, Vinayak Palve, Dylan Grassie, Kanchan Anand, Sylvia Frydman, William R Roush, Ernst Schönbrunn, Matthias Geyer, Derek Duckett, Andrii Monastyrskyi

The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity.

This journal is © The Royal Society of Chemistry.

PMID: 39450271

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