PXD045327

PXD045327 is an original dataset announced via ProteomeXchange.

Title	Design and development of IKZF2 and CK1α dual degraders
Description	Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the rational design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α) in acute myeloid leukemia MOLM-13 cells. Using a structure-based approach, we identified a key naphthamide scaffold that depleted both intended targets. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound, termed DEG-35. A subsequent scaffold replacement campaign informed by degradation profiles against a panel of substrates identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in diffuse large B cell lymphoma (DLBCL) cell line OCI-LY3 and ovarian cancer cell line A2780, indicating that these dual degraders and their targets may have efficacy against additional cancer types.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:19:17.256.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christina Woo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-12 14:04:06	ID requested
1	2024-01-04 07:07:09	announced
⏵ 2	2024-10-22 06:19:18	announced	2024-10-22: Updated project metadata.

10.1021/acs.jmedchem.3c01736;

Miyamoto DK, Curnutt NM, Park SM, Stavropoulos A, Kharas MG, Woo CM, Dual Degraders. J Med Chem, 66(24):16953-16979(2023) [pubmed]

submitter keyword: Protein degradation, molecular glue

Christina Woo
contact affiliation	Department of Chemistry and Chemical Biology, Harvard University
contact email	cwoo@chemistry.harvard.edu
lab head
Christina Woo
contact affiliation	Harvard University
contact email	cwoo@chemistry.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045327
     1. Label: PRIDE project
     2. Name: Design and development of IKZF2 and CK1α dual degraders