2. Academic Validation
  3. Recruitment of FBXO22 for targeted degradation of NSD2

Recruitment of FBXO22 for targeted degradation of NSD2

  • Nat Chem Biol. 2024 Jul 4. doi: 10.1038/s41589-024-01660-y.
David Y Nie # 1 2 3,  John R Tabor # 4,  Jianping Li 5 6,  Maria Kutera 1 2 3,  Jonathan St-Germain 2,  Ronan P Hanley 4 7,  Esther Wolf 8,  Ethan Paulakonis 9,  Tristan M G Kenney 1 2 3,  Shili Duan 1 2,  Suman Shrestha 1 2,  Dominic D G Owens 1 10,  Matthew E R Maitland 1,  Ailing Pon 1,  Magdalena Szewczyk 1,  Anthony Joseph Lamberto 5,  Michael Menes 5,  Fengling Li 1,  Linda Z Penn 2 3,  Dalia Barsyte-Lovejoy 1 11,  Nicholas G Brown 9 12,  Anthony M Barsotti 13,  Andrew W Stamford 13,  Jon L Collins 14,  Derek J Wilson 8,  Brian Raught 2 3,  Jonathan D Licht 5,  Lindsey I James 15 16,  Cheryl H Arrowsmith 17 18 19
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 2 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 3 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 4 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, NC, USA.
  • 5 University of Florida Health Cancer Center, Gainesville, FL, USA.
  • 6 Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 7 C4 Therapeutics, Watertown, MA, USA.
  • 8 Department of Chemistry, York University, Toronto, Ontario, Canada.
  • 9 Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
  • 10 Amphista Therapeutics, Cambridge, UK.
  • 11 Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 12 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 13 Deerfield Discovery and Development, Deerfield Management, New York, NY, USA.
  • 14 Office of the Vice Chancellor for Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 15 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, NC, USA. ingerman@email.unc.edu.
  • 16 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ingerman@email.unc.edu.
  • 17 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. cheryl.arrowsmith@uhn.ca.
  • 18 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. cheryl.arrowsmith@uhn.ca.
  • 19 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. cheryl.arrowsmith@uhn.ca.
  • # Contributed equally.
PMID: 38965384 DOI: 10.1038/s41589-024-01660-y
Abstract

Targeted protein degradation (TPD) is an emerging therapeutic strategy that would benefit from new chemical entities with which to recruit a wider variety of ubiquitin E3 Ligases to target proteins for proteasomal degradation. Here we describe a TPD strategy involving the recruitment of FBXO22 to induce degradation of the Histone Methyltransferase and oncogene NSD2. UNC8732 facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, Apoptosis and reversal of drug resistance. The primary amine of UNC8732 is metabolized to an aldehyde species, which engages C326 of FBXO22 to recruit the SCFFBXO22 Cullin complex. We further demonstrate that a previously reported alkyl amine-containing degrader targeting XIAP is similarly dependent on SCFFBXO22. Overall, we present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes and a new FBXO22-recruitment strategy for TPD.

Figures
Products
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  • HY-161796
    促蛋白质降解
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