Design principles for cyclin K molecular glue degraders

Author:

Kozicka ZuzannaORCID,Suchyta Dakota J.,Focht Vivian,Kempf Georg,Petzold Georg,Jentzsch Marius,Zou Charles,Di Genua Cristina,Donovan Katherine A.ORCID,Coomar Seemon,Cigler MarkoORCID,Mayor-Ruiz Cristina,Schmid-Burgk Jonathan L.ORCID,Häussinger DanielORCID,Winter Georg E.ORCID,Fischer Eric S.ORCID,Słabicki MikołajORCID,Gillingham DennisORCID,Ebert Benjamin L.ORCID,Thomä Nicolas H.ORCID

Abstract

AbstractMolecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12–cyclin K to the DDB1–CUL4–RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure–activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Molecular Biology

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