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PXD061850

PXD061850 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition
DescriptionIn 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.
HostingRepositoryPRIDE
AnnounceDate2025-03-18
AnnouncementXMLSubmission_2025-03-18_08:52:11.818.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD061850
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterEric Bonneil
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02025-03-14 09:46:36ID requested
12025-03-18 08:52:12announced
Publication List
10.6019/PXD061850;
Keyword List
submitter keyword: Molecular Glue Degrader, CDK12, DDB1, Cyclin K, Acute Myeloid Leukemia
Contact List
Guy Sauvageau
contact affiliationIRIC-Université de Montréal
contact emailguy.sauvageau@umontreal.ca
lab head
Eric Bonneil
contact affiliationProteomic Platform
contact emaileric.bonneil@umontreal.ca
dataset submitter
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Dataset FTP location
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