2. Academic Validation
  3. Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3

Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3

  • Nat Chem Biol. 2019 Aug;15(8):822-829. doi: 10.1038/s41589-019-0310-x.
Jark Böttcher 1,  David Dilworth 2,  Ulrich Reiser 3,  Ralph A Neumüller 3,  Michael Schleicher 3,  Mark Petronczki 3,  Markus Zeeb 4,  Nikolai Mischerikow 3,  Abdellah Allali-Hassani 2,  Magdalena M Szewczyk 2,  Fengling Li 2,  Steven Kennedy 2,  Masoud Vedadi 2 5,  Dalia Barsyte-Lovejoy 2,  Peter J Brown 2,  Kilian V M Huber 6 7,  Catherine M Rogers 6 7,  Carrow I Wells 8,  Oleg Fedorov 6 7,  Klaus Rumpel 3,  Andreas Zoephel 3,  Moriz Mayer 3,  Tobias Wunberg 3,  Dietrich Böse 3,  Stephan Zahn 3,  Heribert Arnhof 3,  Helmut Berger 3,  Christoph Reiser 3,  Alexandra Hörmann 3,  Teresa Krammer 3,  Maja Corcokovic 3,  Bernadette Sharps 3,  Sandra Winkler 3,  Daniela Häring 3,  Xiao-Ling Cockcroft 3,  Julian E Fuchs 3,  Barbara Müllauer 3,  Alexander Weiss-Puxbaum 3,  Thomas Gerstberger 3,  Guido Boehmelt 3,  Christopher R Vakoc 9,  Cheryl H Arrowsmith 2 10,  Mark Pearson 3,  Darryl B McConnell 3
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. jark.boettcher@boehringer-ingelheim.com.
  • 2 Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
  • 3 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 4 Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 6 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 7 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 8 Structural Genomics Consortium, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 9 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
  • 10 Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
PMID: 31285596 DOI: 10.1038/s41589-019-0310-x
Abstract

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung Cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in Cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

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