PXD021901-1

PXD021901 is an original dataset announced via ProteomeXchange.

Title	An NSD3-targeting PROTAC suppresses the NSD3 and cMyc oncogenic nodes in cancer cells
Description	Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in cancers, encodes a chromatin modulator and an attractive onco-target. However, agent that can effectively suppress the NSD3-mediated oncogenic actions is currently lacking. We report an NSD3-targeting proteolysis targeting chimera (PROTAC), termed MS9715, which achieves effective and specific depletion of NSD3 and interacting partners (including cMyc) in tumor cells. MS9715-induced NSD3 degradation relies on BI-9321, an antagonist module binding the PWWP1 domain of NSD3, and VHL, which is chemically conjugated to BI-9321 via a linker and VHL ligand module. Importantly, compared to BI-9321, a recently disclosed NSD3 antagonist, MS9715 is more potent in suppressing growth of the NSD3-dependent hematological cancer including models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), and uniquely mediate simultaneous depletion of cellular NSD3 and cMyc. Transcriptome profiling further demonstrates effective actions of MS9715 but not BI-9321 in suppressing both NSD3- and cMyc-associated gene-expression programs, a phenomenon reminiscent of the CRISPR/cas9-mediated knockout (KO) of NSD3. Together, this study reports a first-in-class NSD3 PROTAC/degrader suitable for co-suppressing NSD3- and cMyc-related oncogenic nodes in cancer cells, suggesting a novel therapeutic strategy.
HostingRepository	PRIDE
AnnounceDate	2021-08-27
AnnouncementXML	Submission_2021-08-27_05:51:44.198.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD021901
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Stephanie Byrum
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	2020-10-08 08:21:32	ID requested
⏵ 1	2021-08-27 05:51:44	announced

Dataset with its publication pending

submitter keyword: Chromatin, histone, NSD3, cMyc, epigenetics, PROTAC, degrader

Gang Greg Wang
contact affiliation	1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA 2Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
contact email	greg_wang@med.unc.edu
lab head
Stephanie Byrum
contact affiliation	UAMS
contact email	sbyrum@uams.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021901
     1. Label: PRIDE project
     2. Name: An NSD3-targeting PROTAC suppresses the NSD3 and cMyc oncogenic nodes in cancer cells