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

  • Cell Chem Biol. 2022 Mar 17;29(3):386-397.e9. doi: 10.1016/j.chembiol.2021.08.004.
Chenxi Xu  1 ,  Fanye Meng  2 ,  Kwang-Su Park  2 ,  Aaron J Storey  3 ,  Weida Gong  4 ,  Yi-Hsuan Tsai  4 ,  Elisa Gibson  5 ,  Stephanie D Byrum  3 ,  Dongxu Li  1 ,  Rick D Edmondson  3 ,  Samuel G Mackintosh  3 ,  Masoud Vedadi  6 ,  Ling Cai  7 ,  Alan J Tackett  3 ,  H Ümit Kaniskan  8 ,  Jian Jin  9 ,  Gang Greg Wang  10
Affiliations
  • 1. Lineberger 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.
  • 2. 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, NY 10029, USA.
  • 3. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
  • 4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 5. Structural Genomics Consortium, University of Toronto, Toronto ON M5G 1L7, Canada.
  • 6. Structural Genomics Consortium, University of Toronto, Toronto ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto ON M5S 1A8, Canada.
  • 7. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 8. 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, NY 10029, USA. Electronic address: [email protected].
  • 9. 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, NY 10029, USA. Electronic address: [email protected].
  • 10. Lineberger 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; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
PMID: 34469831 DOI: 10.1016/j.chembiol.2021.08.004
Abstract

Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated oncogenic actions are currently lacking. We report the NSD3-targeting proteolysis targeting chimera (PROTAC), MS9715, which achieves effective and specific targeting of NSD3 and associated cMyc node in tumor cells. MS9715 is designed by linking BI-9321, a NSD3 antagonist, which binds NSD3's PWWP1 domain, with an E3 Ligase VHL ligand. Importantly, MS9715, but not BI-9321, effectively suppresses growth of NSD3-dependent hematological Cancer cells. Transcriptomic profiling demonstrates that MS9715, but not BI-9321, effectively suppresses NSD3-and cMyc-associated gene expression programs, resembling effects of the CRISPR-Cas9-mediated knockout of NSD3. Collectively, these results suggest that pharmacological degradation of NSD3 as an attractive therapeutic strategy, which co-suppresses NSD3- and cMyc-related oncogenic nodes, is superior to blocking the PWWP1 domain of NSD3.

Keywords
NSD3; PROTAC; cMyc; cancer; chromatin; degrader; epigenetics; histone; ubiquitylation.
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