2. Academic Validation
  3. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

  • Nat Chem Biol. 2022 Jan;18(1):56-63. doi: 10.1038/s41589-021-00898-0.
David Dilworth  # 1 2,  Ronan P Hanley  # 3 4,  Renato Ferreira de Freitas  # 5 6,  Abdellah Allali-Hassani  # 5 7,  Mengqi Zhou  # 5 8,  Naimee Mehta 3 9,  Matthew R Marunde 10,  Suzanne Ackloo 5,  Raquel Arminda Carvalho Machado 5,  Aliakbar Khalili Yazdi 5,  Dominic D G Owens 5,  Victoria Vu 5,  David Y Nie 5 11,  Mona Alqazzaz 5,  Edyta Marcon 12,  Fengling Li 5,  Irene Chau 5,  Albina Bolotokova 5,  Su Qin 5 13,  Ming Lei 5 8,  Yanli Liu 5 14,  Magdalena M Szewczyk 5,  Aiping Dong 5,  Sina Kazemzadeh 3,  Tigran Abramyan 3 15,  Irina K Popova 10,  Nathan W Hall 10,  Matthew J Meiners 10,  Marcus A Cheek 10,  Elisa Gibson 5,  Dmitri Kireev 3,  Jack F Greenblatt 12,  Michael-C Keogh 10,  Jinrong Min 5 8,  Peter J Brown 5,  Masoud Vedadi 5 16,  Cheryl H Arrowsmith 5 17,  Dalia Barsyte-Lovejoy 18 19,  Lindsey I James 20,  Matthieu Schapira 21 22
Affiliations

Affiliations

  • 1 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 2 BlueRock Therapeutics, Toronto, Ontario, Canada. [email protected].
  • 3 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.
  • 4 C4 Therapeutics, Watertown, MA, USA.
  • 5 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 6 Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Rua Arcturus 3, São Bernardo do Campo, Brazil.
  • 7 Incyte, Wilmington, DE, USA.
  • 8 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, China.
  • 9 Nurix Therapeutics, San Francisco, CA, USA.
  • 10 EpiCypher Inc., Durham, NC, USA.
  • 11 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 12 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • 13 Life Science Research Center, Southern University of Science and Technology, Shenzhen, China.
  • 14 College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 15 Atomwise, San Francisco, CA, USA.
  • 16 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 17 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 18 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 19 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 20 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. [email protected].
  • 21 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • 22 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. [email protected].
  • # Contributed equally.
PMID: 34782742 DOI: 10.1038/s41589-021-00898-0
Abstract

Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary Enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.

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