PXD039474

PXD039474 is an original dataset announced via ProteomeXchange.

Title	Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells
Description	Acute 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.
HostingRepository	PRIDE
AnnounceDate	2023-03-08
AnnouncementXML	Submission_2023-03-08_09:00:34.937.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	DavidMiyamoto
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-16 08:18:31	ID requested
⏵ 1	2023-03-08 09:00:35	announced

Dataset with its publication pending

submitter keyword: targeted protein degradation

acute myeloid leukemia

casein kinase 1 alpha

IKZF2

ChristinaWoo
contact affiliation	Harvard University
contact email	cwoo@chemistry.harvard.edu
lab head
DavidMiyamoto
contact affiliation	Harvard University
contact email	davidmiyamoto@g.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD039474
     1. Label: PRIDE project
     2. Name: Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells