ArticleNature chemical biology2024
Recruitment of FBXO22 for targeted degradation of NSD2.
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Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38 citing papers in PubMed.
- Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation.Nature chemical biology · 2026Article
- Charged molecular glue discovery enabled by targeted degron display.Nature chemical biology · 2026Article
- High-throughput ligand diversification to discover chemical inducers of proximity.Nature chemical biology · 2026Article
- A New Recruitable E3 Ligase UHRF1 Supporting Targeted Protein Degradation: A Minimal Azide as a Recruitment Ligand.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Proteomics-Driven Strategies for Proximity-Inducing Drug Discovery.Angewandte Chemie (International ed. in English) · 2026Review
- Aryl Aldehyde-Anchored Small Molecules Recruit FBXO22 for Targeted Degradation of NSD2.Journal of medicinal chemistry · 2026Article
- Covalent Reprogramming of Kinase Binders to Modulate Protein Abundance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Structural basis of NSD2 degradation via targeted recruitment of SCF-FBXO22.Nature communications · 2026Article
- Harnessing FBXO31 with Terminal Amide-Functionalized Molecules for Targeted Protein Degradation.Journal of the American Chemical Society · 2026Article
- Identification of E3 ligase substrates and PROTAC-induced ubiquitylation sites using proximity-based identification of ubiquitin sites (PrIUS).Communications biology · 2026Article
- Small-molecule degraders for oncogenic KRASNature communications · 2026Article
- Sub-stoichiometric Degradation is Dispensable for Potent PROTACs: A Case Study for Irreversible Covalent BTK Degraders.bioRxiv : the preprint server for biology · 2026Article
- Epigenetic reprogramming in multiple myeloma-Challenges and opportunities.International journal of cancer · 2026Review
- Article
- Recent advances in targeting protein degradation for tumor immunotherapy.Journal of hematology & oncology · 2025Review
- Covalent Reprogramming of Kinase Binders to Modulate Protein Homeostasis.bioRxiv : the preprint server for biology · 2025Article
- NSD Family-Mediated H3K36 Methylation in Human Cancer: Mechanisms and Therapeutic Opportunities.Biomedicines · 2025Review
- Rational design of potent small-molecule SMARCA2/A4 degraders acting via the recruitment of FBXO22.Nature communications · 2025Article
- E3 ubiquitin ligases in signaling, disease, and therapeutics.Trends in biochemical sciences · 2025Review
- Mode of action of a DCAF16-recruiting targeted glue that can selectively degrade BRD9.Nature communications · 2025Article
Corrections and comments
- Update of
Authors and funding
29 authors.
David Y Nie *Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-6956-0634
John R Tabor *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.
Jianping LiUniversity of Florida Health Cancer Center, Gainesville, FL, USA.ORCID http://orcid.org/0000-0002-3972-1652
Maria KuteraStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Jonathan St-GermainPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Ronan P HanleyCenter 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.
Esther WolfDepartment of Chemistry, York University, Toronto, Ontario, Canada.
Ethan PaulakonisDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
Tristan M G KenneyStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0001-8242-4349
Shili DuanStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Suman ShresthaStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Dominic D G OwensStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0001-6194-4636
Matthew E R MaitlandStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Ailing PonStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Magdalena SzewczykStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Anthony Joseph LambertoUniversity of Florida Health Cancer Center, Gainesville, FL, USA.ORCID http://orcid.org/0009-0008-2950-0013
Michael MenesUniversity of Florida Health Cancer Center, Gainesville, FL, USA.
Fengling LiStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Linda Z PennPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Dalia Barsyte-LovejoyStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-6560-9621
Nicholas G BrownDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-6141-0164
Anthony M BarsottiDeerfield Discovery and Development, Deerfield Management, New York, NY, USA.
Andrew W StamfordDeerfield Discovery and Development, Deerfield Management, New York, NY, USA.ORCID http://orcid.org/0000-0003-0693-3461
Jon L CollinsOffice of the Vice Chancellor for Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0009-0007-8086-1802
Derek J WilsonDepartment of Chemistry, York University, Toronto, Ontario, Canada.ORCID http://orcid.org/0000-0002-7012-6085
Brian RaughtPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Jonathan D LichtUniversity of Florida Health Cancer Center, Gainesville, FL, USA.ORCID http://orcid.org/0000-0002-3942-1369
Lindsey I JamesCenter 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.ORCID http://orcid.org/0000-0002-6034-7116
Cheryl H ArrowsmithStructural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. cheryl.arrowsmith@uhn.ca.ORCID http://orcid.org/0000-0002-4971-3250
Funding
Cancer Epigenetics Training GrantT32CA217824 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WEISSMAN, BERNARD E. · 2017 to 2021
$1.8MDISCOVERY OF FIRST-IN-CLASS NSD2 DEGRADERS FOR CANCER THERAPYR01CA242305 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JAMES, LINDSEY INGERMAN · 2019 to 2024
$1.7MCancer Research Society (Société de Recherche sur le Cancer) 25418Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec) 320128Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) 494204Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) FDN154328Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) OGB190363Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) PJT156093Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada) CRDPJ-504037Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada) RGPIN-480432NCI NIH HHS R01 CA242305NCI NIH HHS T32 CA217824UNC | UNC-Chapel Hill | Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (UNC Lineberger Comprehensive Cancer Center) 5T32CA217824-05U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01CA242305
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 SCF
Indexed as
Histone-Lysine N-MethyltransferaseProteolysisApoptosisCell Line, TumorF-Box ProteinsHumansPrecursor Cell Lymphoblastic Leukemia-LymphomaReceptors, Cytoplasmic and NuclearRepressor ProteinsF-Box ProteinsFBXO22 protein, humanHistone-Lysine N-MethyltransferaseNSD2 protein, humanReceptors, Cytoplasmic and NuclearRepressor Proteins
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