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A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells

Chenxi Xu1, Fanye Meng2, Kwang-Su Park2

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

Cell Chemical Biology
|September 1, 2021
PubMed

Insights

A novel proteolysis targeting chimera (PROTAC), MS9715, effectively degrades Nuclear Receptor Binding SET Domain Protein 3 (NSD3) and cMyc in cancer cells. This NSD3 PROTAC offers a superior therapeutic strategy compared to simple antagonism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Nuclear receptor binding SET domain protein 3 (NSD3) is a chromatin modulator located in the 8p11-p12 amplicon, frequently amplified in human cancers.
  • NSD3 is an attractive therapeutic target due to its oncogenic functions, but effective suppressive agents are lacking.

Purpose of the Study:

  • To develop and evaluate a novel NSD3-targeting proteolysis targeting chimera (PROTAC) for cancer therapy.
  • To investigate the efficacy of NSD3 degradation compared to direct antagonism.

Main Methods:

  • Design and synthesis of MS9715, a PROTAC linking a NSD3 antagonist (BI-9321) to an E3 ligase (VHL) ligand.
  • Assessment of MS9715's efficacy in suppressing NSD3-dependent hematological cancer cell growth.
  • Transcriptomic profiling to analyze gene expression changes induced by MS9715 and BI-9321.

Main Results:

  • MS9715 effectively targets NSD3 and the associated cMyc node in tumor cells.
  • MS9715, unlike the antagonist BI-9321, significantly suppresses the growth of NSD3-dependent hematological cancer cells.
  • MS9715 treatment leads to suppression of NSD3- and cMyc-associated gene expression programs, mimicking NSD3 knockout effects.

Conclusions:

  • Pharmacological degradation of NSD3 using PROTACs represents a promising therapeutic strategy for cancers driven by NSD3.
  • Co-suppression of NSD3 and cMyc oncogenic nodes via PROTAC-mediated degradation is superior to PWWP1 domain antagonism.
  • NSD3 PROTACs offer a potent approach to target NSD3-driven oncogenesis.
Keywords:
NSD3PROTACcMyccancerchromatindegraderepigeneticshistoneubiquitylation

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