In a study published in Nature Chemical Biology, Kozicka et al. have unraveled the structural principles governing molecular glue degraders, a promising therapeutic modality for targeted protein degradation. By systematically evaluating over 90 chemically diverse compounds, they discovered that all effective cyclin K degraders simultaneously bind to CDK12 and engage the DDB1 interfacial residue Arg928, inducing a cooperative interaction with the DDB1-CUL4-RBX1 E3 ligase complex.

The study unveiled that a wide range of scaffolds, including kinase inhibitors and small fragments, can acquire this “molecular glue” activity, bridging CDK12 and DDB1. Crystallographic analyses of 28 ternary complexes revealed a common binding mode, with the compounds’ “gluing moieties” engaging Arg928 through π-cation, hydrogen bonding, or hydrophobic interactions.

The researchers demonstrated that cyclin K degraders exhibit distinct transcriptional signatures from CDK12 inhibitors, offering unique therapeutic opportunities. Importantly, they identified several potent and selective degraders, outperforming the previously reported CR8 scaffold.

This comprehensive structure-activity relationship analysis provides a conceptual framework for rational molecular glue design, paving the way for developing targeted protein degraders as potential therapeutics.

The study utilized the IonOpticks Aurora Ultimate CSI 25 cm UHPLC column for high-resolution separation and analysis.

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Publication
Nature chemical biology

Authors

Zuzanna Kozicka; Dakota J. Suchyta; Vivian Focht; Georg Kempf; Georg Petzold; Marius Jentzsch; Charles Zou; Cristina Di Genua; Katherine A. Donovan; Seemon Coomar; Marko Cigler; Cristina Mayor-Ruiz; Jonathan L. Schmid-Burgk; Daniel Häussinger; Georg E. Winter; Eric S. Fischer; Mikołaj Słabicki; Dennis Gillingham; Benjamin L. Ebert; Nicolas H. Thomä

Title

Design principles for cyclin K molecular glue degraders