Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.
Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.
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DOI：
10.1021/acs.jmedchem.0c01768
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发表时间：
2021-02-11
影响因子：
7.3
通讯作者：
Allali-Hassani A
中科院分区：
文献类型：
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作者：
Ferreira de Freitas R;Liu Y;Szewczyk MM;Mehta N;Li F;McLeod D;Zepeda-Velázquez C;Dilworth D;Hanley RP;Gibson E;Brown PJ;Al-Awar R;James LI;Arrowsmith CH;Barsyte-Lovejoy D;Min J;Vedadi M;Schapira M;Allali-Hassani A
由易位和激活突变驱动的赖氨酸甲基转移酶NSD2活性增加与多发性骨髓瘤和急性淋巴细胞白血病有关，但迄今为止还没有针对NSD2的化学探针的报道。在这里，我们提出了第一个阻断NSD2的n端PWWP结构域与H3K36me2之间蛋白-蛋白相互作用的拮抗剂。通过虚拟筛选和实验验证，我们发现了小分子拮抗剂3f，它以3.4 μM的Kd与NSD2-PWWP1结构域结合，并在细胞中消除组蛋白H3K36me2与PWWP1结构域的结合。本研究建立了一种靶向NSD2的替代方法，并提供了一种小分子拮抗剂，可以进一步优化为化学探针，以更好地了解该蛋白的细胞功能。
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.