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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月28日

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  • Céline Moison,
  • Rodrigo Mendoza-Sanchez,
  • Deanne Gracias,
  • Doris A Schuetz,
  • Jean-François Spinella,
  • Simon Girard,
  • Bounkham Thavonekham,
  • Jalila Chagraoui,
  • Aurélie Durand,
  • Simon Fortier,
  • Tara MacRae,
  • Eric Bonneil,
  • Yannick Rose,
  • Nadine Mayotte,
  • Isabel Boivin,
  • Pierre Thibault,
  • Josée Hébert,
  • Réjean Ruel,
  • Anne Marinier,
  • Guy Sauvageau

摘要

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.