PXD039474-1

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD039474

PRIDE project URI

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