2. Academic Validation
  3. DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition

DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition

  • EMBO Rep. 2025 Jun;26(11):2836-2854. doi: 10.1038/s44319-025-00448-y.
Céline Moison # 1,  Rodrigo Mendoza-Sanchez # 1,  Deanne Gracias # 1,  Doris A Schuetz 1,  Jean-François Spinella 1,  Simon Girard 1,  Bounkham Thavonekham 1,  Jalila Chagraoui 1,  Aurélie Durand 1,  Simon Fortier 1,  Tara MacRae 1,  Eric Bonneil 1,  Yannick Rose 1,  Nadine Mayotte 1,  Isabel Boivin 1,  Pierre Thibault 1 2,  Josée Hébert 1 3 4 5,  Réjean Ruel 1,  Anne Marinier 6 7,  Guy Sauvageau 8 9 10 11
Affiliations

Affiliations

  • 1 Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
  • 2 Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada.
  • 3 Institut universitaire d'hémato-oncologie et de thérapie cellulaire, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
  • 4 Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.
  • 5 Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
  • 6 Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada. anne.marinier@umontreal.ca.
  • 7 Department of Chemistry, Université de Montréal, Montreal, Quebec, Canada. anne.marinier@umontreal.ca.
  • 8 Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada. guy.sauvageau@umontreal.ca.
  • 9 Institut universitaire d'hémato-oncologie et de thérapie cellulaire, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada. guy.sauvageau@umontreal.ca.
  • 10 Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada. guy.sauvageau@umontreal.ca.
  • 11 Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada. guy.sauvageau@umontreal.ca.
  • # Contributed equally.
PMID: 40295725 DOI: 10.1038/s44319-025-00448-y
Abstract

In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.

Keywords

Acute Myeloid Leukemia; CDK12; Cyclin K; DDB1; Molecular Glue Degrader.

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