2. Academic Validation
  3. Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2

Discovery of a Potent and Selective Targeted NSD2 Degrader for the Reduction of H3K36me2

  • J Am Chem Soc. 2023 Apr 12;145(14):8176-8188. doi: 10.1021/jacs.3c01421.
Ronan P Hanley 1,  David Y Nie 2 3 4,  John R Tabor 1,  Fengling Li 2,  Amin Sobh 5,  Chenxi Xu 6 7,  Natalie K Barker 8,  David Dilworth 2,  Taraneh Hajian 2,  Elisa Gibson 2,  Magdalena M Szewczyk 2,  Peter J Brown 2,  Dalia Barsyte-Lovejoy 2 9,  Laura E Herring 8,  Gang Greg Wang 6 7 10,  Jonathan D Licht 5,  Masoud Vedadi 2 9,  Cheryl H Arrowsmith 2 3 4,  Lindsey I James 1 6
Affiliations

Affiliations

  • 1 Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 1L7, Canada.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • 5 University of Florida Health Cancer Center, The University of Florida Cancer and Genetics Research Complex, Gainesville, Florida 32610, United States.
  • 6 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 7 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 8 UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 9 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 10 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
PMID: 36976643 DOI: 10.1021/jacs.3c01421
Abstract

Nuclear receptor-binding SET domain-containing 2 (NSD2) plays important roles in gene regulation, largely through its ability to dimethylate lysine 36 of histone 3 (H3K36me2). Despite aberrant activity of NSD2 reported in numerous cancers, efforts to selectively inhibit the catalytic activity of this protein with small molecules have been unsuccessful to date. Here, we report the development of UNC8153, a novel NSD2-targeted degrader that potently and selectively reduces the cellular levels of both NSD2 protein and the H3K36me2 chromatin mark. UNC8153 contains a simple warhead that confers proteasome-dependent degradation of NSD2 through a novel mechanism. Importantly, UNC8153-mediated reduction of H3K36me2 through the degradation of NSD2 results in the downregulation of pathological phenotypes in multiple myeloma cells including mild antiproliferative effects in MM1.S cells containing an activating point mutation and antiadhesive effects in KMS11 cells harboring the t(4;14) translocation that upregulates NSD2 expression.

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