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首页> 外文期刊>RSC Advances >ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth
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ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth

机译：ZLD1122，一种新型EZH2和EZH1小分子抑制剂，阻断H3K27甲基化和弥漫性大B细胞淋巴瘤细胞生长

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摘要

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been reported to be overexpressed in a variety of cancers and is associated with tumor malignancy. This is mainly because EZH2 catalyzes the hypertrimethylation of histone 3 at lysine 27 (H3K27) at the promoter of target genes, leading to the silencing of downstream tumor suppressor genes. Hence, blocking its catalytic function may be a therapeutic strategy for the treatment of tumors which over-express or have a gain-of-function mutation in EZH2, such as lymphomas. Here, we reported a novel, selective, small-molecule inhibitor of EZH2 and EZH1 synthesized by us, ZLD1122, which inhibited both EZH1 and wild type and mutant EZH2 activities with nanomolar potency. ZLD1122 significantly inhibited intracellular H3K27 trimethylation without affecting the levels of H3, H3K9me3, and H3K4me3, indicating its selective inhibition of polycomb repressive complex 2 (PRC2) methyl catalytic function. Moreover, ZLD1122 induced G0/G1 phase arrest in diffuse large B cell lymphoma (DLBCL) cells in a dose-dependent manner via downregulation of cyclinE and CDK4 as well as upregulation of p21 and cyclinD1. Furthermore, it induced apoptosis and loss of mitochondrial membrane potential (Delta psi(m)), and elevated the levels of cleaved caspase-9 in Su-DHL-6 and Pfeiffer cells, suggesting that ZLD1122 suppresses the viability of DLBCL cells by inducing caspase-mediated intrinsic apoptosis. Taken together, these data demonstrated that ZLD1122, owing to its pharmacologically inhibitory activity against EZH2, could be a promising agent for the treatment of lymphomas with EZH2 gain-of-function mutations.
机译：据报道，Zeste同源物2（EZH2）的组蛋白甲基转移酶增强剂在各种癌症中过表达，与肿瘤恶性肿瘤有关。这主要是因为EZH2在靶基因启动子的赖氨酸27（H3K27）催化组蛋白3的超三维化，导致下游肿瘤抑制基因的沉默。因此，阻断其催化功能可以是治疗肿瘤的治疗策略，其在EZH2（例如淋巴瘤）中过表达或具有功能性突变。在这里，我们报道了由US，ZLD1122合成的EZH2和EZH1的新型，选择性小分子抑制剂，其抑制了EZH1和野生型和突变体EZH2活性的含有纳摩尔效力。 ZLD1122显着抑制细胞内H3K27的三甲基化，而不影响H3，H3K9ME3和H3K4ME3的水平，表明其对PolycomB压抑复合物2（PRC2）甲基催化功能的选择性抑制。此外，ZLD1122在衍射大B细胞淋巴瘤（DLBCL）细胞中诱导G0 / G1相阻滞，通过依赖性方式通过环曲调和CDK4的下调以及P21和Cyclind1的上调。此外，它诱导了细胞凋亡和线粒体膜电位的丧失（Delta psi（m）），并升高了Su-DHL-6和Pfeiffer细胞中切割的Caspase-9水平，表明ZLD1122通过诱导胱天蛋白酶抑制DLBCL细胞的活力 - 介质的内在凋亡。总之，这些数据证明，由于其对EZH2的药理学抑制活性，ZLD1122可以是用EzH2获得功能突变治疗淋巴瘤的有希望的剂。

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  • 来源
    《RSC Advances》 |2016年第34期|共10页
  • 作者

    Gao Tiantao; Zhang Lidan; Zhu Yongxia; Song Xuejiao; Feng Qiang; Lei Qian; Shi Suxia; Deng Hongxia; Xiong Menghua; You Xinyu; Zuo Weiqiong; Liu Li; Peng Cuiting; Wang Ningyu; Ye Tinghong; Xia Yong; Yu Luoting;

  • 作者单位

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Sch Chem Engn Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Sch Chem Engn Chengdu 610041 Peoples R China;

    Sichuan Univ Sch Chem Engn Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

    Sichuan Univ Collaborat Innovat Ctr Biotherapy State Key Lab Biotherapy &

    Canc Ctr West China Hosp West China Med Sch 17 3rd Sect Ren Min South Rd Chengdu 610041 Peoples R China;

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