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PXD039474

PXD039474 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDual IKZF2 and CK1α degrader targets acute myeloid leukemia cells
DescriptionAcute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1 alpha (CK1α) termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cell lines through CK1α–p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or the analog DEG-77 delays leukemia progression in murine and human AML mice models. Overall, we provide a strategy for multi-targeted degradation of IKZF2/CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.
HostingRepositoryPRIDE
AnnounceDate2023-03-08
AnnouncementXMLSubmission_2023-03-08_09:00:34.937.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterDavidMiyamoto
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-01-16 08:18:31ID requested
12023-03-08 09:00:35announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: targeted protein degradation
acute myeloid leukemia
casein kinase 1 alpha
IKZF2
Contact List
ChristinaWoo
contact affiliationHarvard University
contact emailcwoo@chemistry.harvard.edu
lab head
DavidMiyamoto
contact affiliationHarvard University
contact emaildavidmiyamoto@g.harvard.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
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