Related Experiment Video

Updated: Sep 3, 2025

High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines

Published on: November 9, 2020

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Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos

Fanye Meng1, Chenxi Xu2,3, Kwang-Su Park1

  • 1Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Journal of Medicinal Chemistry
|July 27, 2022
PubMed

Insights

Researchers developed a novel PROTAC degrader, compound 9, to target NSD2, a protein overexpressed in multiple myeloma. This new compound effectively degrades NSD2 and inhibits cancer cell growth, offering a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Nuclear receptor binding SET domain protein 2 (NSD2) overexpression is common in multiple myeloma (MM).
  • Current NSD2 inhibitors show limited efficacy in reducing MM cell proliferation.

Purpose of the Study:

  • To discover and characterize a novel NSD2 proteolysis targeting chimera (PROTAC) degrader.
  • To evaluate the efficacy of the PROTAC degrader in suppressing cancer cell growth.

Main Methods:

  • Synthesis and characterization of NSD2 PROTAC degrader (compound 9) and control compounds (17 and 18).
  • Assessment of NSD2 degradation in a concentration-, time-, CRBN-, and proteasome-dependent manner.
  • Evaluation of compound 9's efficacy in inhibiting cancer cell proliferation and its bioavailability in vivo.

Main Results:

  • Compound 9 effectively degraded NSD2, unlike control compounds 17 and 18.
  • Compound 9 demonstrated greater efficacy in suppressing cancer cell growth compared to existing NSD2 binders.
  • Compound 9 exhibited bioavailability in mice.

Conclusions:

  • Compound 9 represents a first-in-class NSD2 PROTAC degrader with significant potential for treating multiple myeloma.
  • Compounds 9, 17, and 18 serve as valuable chemical tools for further research into NSD2's role in diseases.

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