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

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

  • J Med Chem. 2022 Aug 11;65(15):10611-10625. doi: 10.1021/acs.jmedchem.2c00807.
Fanye Meng 1,  Chenxi Xu 2 3,  Kwang-Su Park 1,  H Ümit Kaniskan 1,  Gang Greg Wang 2 3 4,  Jian Jin 1
Affiliations

Affiliations

  • 1 Mount 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.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 35895319 DOI: 10.1021/acs.jmedchem.2c00807
Abstract

Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9 (MS159), and two structurally similar controls, 17 (MS159N1) and 18 (MS159N2), with diminished binding to the Cereblon (CRBN) E3 ligase and NSD2, respectively. Compound 9, but not 17 and 18, effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner. Compound 9 also effectively degraded CRBN neo-substrates IKZF1 and IKZF3, but not GSPT1. Importantly, compound 9 was much more effective in suppressing the growth in Cancer cells than the parent NSD2 binder. Moreover, compound 9 was bioavailable in mice. Altogether, compound 9 and its two controls 17 and 18 are valuable chemical tools for exploring the roles of NSD2 in health and disease.

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