| Literature DB >> 31285596 |
Jark Böttcher1, David Dilworth2, Ulrich Reiser3, Ralph A Neumüller3, Michael Schleicher3, Mark Petronczki3, Markus Zeeb4, Nikolai Mischerikow3, Abdellah Allali-Hassani2, Magdalena M Szewczyk2, Fengling Li2, Steven Kennedy2, Masoud Vedadi2,5, Dalia Barsyte-Lovejoy2, Peter J Brown2, Kilian V M Huber6,7, Catherine M Rogers6,7, Carrow I Wells8, Oleg Fedorov6,7, Klaus Rumpel3, Andreas Zoephel3, Moriz Mayer3, Tobias Wunberg3, Dietrich Böse3, Stephan Zahn3, Heribert Arnhof3, Helmut Berger3, Christoph Reiser3, Alexandra Hörmann3, Teresa Krammer3, Maja Corcokovic3, Bernadette Sharps3, Sandra Winkler3, Daniela Häring3, Xiao-Ling Cockcroft3, Julian E Fuchs3, Barbara Müllauer3, Alexander Weiss-Puxbaum3, Thomas Gerstberger3, Guido Boehmelt3, Christopher R Vakoc9, Cheryl H Arrowsmith2,10, Mark Pearson3, Darryl B McConnell3.
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.Entities:
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Year: 2019 PMID： 31285596 DOI： 10.1038/s41589-019-0310-x
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 16.174