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

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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil

LAB HEAD: Guy Sauvageau

PROVIDER: PXD061850 | Pride | 2025-03-18

REPOSITORIES: Pride

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			Action	DRS
	GS1_F1S1.mzid	Mzid
	GS1_F1S1_R1_4CVs_350-453mz_CV-44-54-64-74_1.mgf	Mgf
	GS1_F1S1_R1_4CVs_350-453mz_CV-44-54-64-74_1.raw	Raw
	GS1_F1S1_R2_6CVs_451-542mz_CV-40-48-56-64-72-80_2.mgf	Mgf
	GS1_F1S1_R2_6CVs_451-542mz_CV-40-48-56-64-72-80_2.raw	Raw

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