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

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.

Authors

Institutions

Publication Details

Journal
EMBO Reports
Published
2025-04-28
DOI
https://doi.org/10.1038/s44319-025-00448-y
Citations
1
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
0.81

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Anne Marinier, Pierre Thibault, Réjean Ruel, Nadine Mayotte et al.
1 citations
EMBO Reports
Protein Degradation and Inhibitors
0.81
article

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

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

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.

EMBO ReportsVol. 26(11)
Hôpital Maisonneuve-Rosemont (CA), Institute for Research in Immunology and Cancer (CA), Université du Québec (CA), Université de Montréal (CA)
Canadian Institutes of Health Research
Openalex Percentile: Top 29%
Protein Degradation and Inhibitors
0.81
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.