| Literature DB >> 33522809 |
Renato Ferreira de Freitas1, Yanli Liu1, Magdalena M Szewczyk1, Naimee Mehta2, Fengling Li1, David McLeod3, Carlos Zepeda-Velázquez3, David Dilworth1, Ronan P Hanley2, Elisa Gibson1, Peter J Brown1, Rima Al-Awar3, Lindsey I James2, Cheryl H Arrowsmith1,4, Dalia Barsyte-Lovejoy1,5, Jinrong Min1,6, Masoud Vedadi1,5, Matthieu Schapira1,5, Abdellah Allali-Hassani1.
Abstract
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 μM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.Entities:
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Year: 2021 PMID： 33522809 PMCID： PMC8130708 DOI： 10.1021/acs.jmedchem.0c01768
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446