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 o

SUBMITTER: Celine Moison 

PROVIDER: S-SCDT-10_1038-S44319-025-00448-Y | biostudies-other |

REPOSITORIES: biostudies-other