Proteomics

Dataset Information

0

An NSD3-targeting PROTAC suppresses the NSD3 and cMyc oncogenic nodes in cancer cells


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Stephanie Byrum  

LAB HEAD: Gang Greg Wang

PROVIDER: PXD021901 | Pride | 2021-08-27

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
Wang_062520_SF01.raw Raw
Wang_062520_SF02.raw Raw
Wang_062520_SF03.raw Raw
Wang_062520_SF04.raw Raw
Wang_062520_SF05.raw Raw
Items per page:
1 - 5 of 20

Similar Datasets

2023-06-26 | PXD036741 | Pride
2022-02-17 | PXD027202 | Pride
2022-08-12 | PXD029576 | Pride
2024-01-26 | PXD038483 | Pride
2022-03-15 | PXD031699 | Pride
2021-08-31 | GSE158296 | GEO
2024-03-12 | PXD049976 | Pride
2022-04-04 | PXD030935 | Pride
2024-05-24 | PXD039385 | Pride
2021-12-29 | GSE180447 | GEO