PXD061850-1

PXD061850 is an original dataset announced via ProteomeXchange.

Title	DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-03-18
AnnouncementXML	Submission_2025-03-18_08:52:11.818.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD061850
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Eric Bonneil
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-14 09:46:36	ID requested
⏵ 1	2025-03-18 08:52:12	announced

10.6019/PXD061850;

submitter keyword: Molecular Glue Degrader, CDK12, DDB1, Cyclin K, Acute Myeloid Leukemia

Guy Sauvageau
contact affiliation	IRIC-Université de Montréal
contact email	guy.sauvageau@umontreal.ca
lab head
Eric Bonneil
contact affiliation	Proteomic Platform
contact email	eric.bonneil@umontreal.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061850
     1. Label: PRIDE project
     2. Name: DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition