2. Academic Validation
  3. Design principles for cyclin K molecular glue degraders

Design principles for cyclin K molecular glue degraders

  • Nat Chem Biol. 2023 Sep 7. doi: 10.1038/s41589-023-01409-z.
Zuzanna Kozicka 1 2,  Dakota J Suchyta 1 3,  Vivian Focht 1,  Georg Kempf 1,  Georg Petzold 1 4,  Marius Jentzsch 5,  Charles Zou 6 7,  Cristina Di Genua 6 8 9,  Katherine A Donovan 10 11,  Seemon Coomar 1,  Marko Cigler 12,  Cristina Mayor-Ruiz 12 13,  Jonathan L Schmid-Burgk 5,  Daniel Häussinger 3,  Georg E Winter 12,  Eric S Fischer 10 11,  Mikołaj Słabicki 6 8,  Dennis Gillingham 3,  Benjamin L Ebert 6 8 14,  Nicolas H Thomä 15
Affiliations

Affiliations

  • 1 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 2 Department of Biology, University of Basel, Basel, Switzerland.
  • 3 Department of Chemistry, University of Basel, Basel, Switzerland.
  • 4 Monte Rosa Therapeutics, Basel, Switzerland.
  • 5 Institute of Clinical Chemistry and Clinical Pharmacology, University and University Hospital Bonn, Bonn, Germany.
  • 6 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 7 Yale University, New Haven, CT, USA.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9 VantAI, New York, NY, USA.
  • 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 12 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 13 IRB Barcelona-Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 14 Howard Hughes Medical Institute, Boston, MA, USA.
  • 15 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. [email protected].
PMID: 37679459 DOI: 10.1038/s41589-023-01409-z
Abstract

Molecular 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.

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