Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns.,Chemical Biology & Drug Design

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Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-05-11 , DOI: 10.1111/cbdd.13702
Yan Zhou ₁ , Dao-Hai Du ₂ , Jia Wang ₁ , Xiao-Qing Cai ₁ , Alicia X Deng ₁ , Olivier Nosjean ₃ , Jean A Boutin ₃ , Pierre Renard ₃ , De-Hua Yang ₁ , Cheng Luo ₂ , Ming-Wei Wang _{1,

4}

Affiliation

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) along with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), which implements transcriptional repression mainly by depositing tri-methylation marks at lysine 27 of histone H3 (H3K27me3). Its catalytic activity is closely correlated to the stability of PRC2 and somatic activating mutation of EZH2 Y641F within the catalytic SET domain drives tumor aggressiveness, drug resistance and poor prognosis. Here, we report two high-throughput screening (HTS) campaigns targeting EZH2 Y641F and EZH2-EED interaction, respectively. For the EZH2 Y641F mutant, the HTS campaign involved a library of 250,000 compounds using a homogenous time-resolved fluorescence (HTRF) assay and identified 162 hits, while 60,160 compounds were screened against EZH2-EED interaction with a fluorescence polarization (FP) assay resulting in 97 hits. Among the 162 EZH2 Y641F inhibitors, 38 also suppressed EZH2-EED interaction and 80 showed inhibitory effects on the wide-type (WT) EZH2. Meanwhile, 10 of the 97 EZH2-EED interaction inhibitors were active against WT EZH2. These hit compounds provide useful tools for the development of novel PRC2-EZH2 inhibitors targeting its catalytic and non-catalytic activities.

中文翻译：

通过多次高通量筛选活动鉴定针对PRC2-EZH2复合物的催化和非催化活性抑制剂。

zeste同源物2（EZH2）的增强子是多梳阻抑复合物2（PRC2）的催化亚基，以及胚外胚层发育（EED）和zeste 12（SUZ12）的抑制剂，后者主要通过在三聚甲基化标记上沉积三甲基化标记来实现转录抑制组蛋白H3（H3K27me3）的赖氨酸27。它的催化活性与PRC2的稳定性密切相关，EZH2 Y641F在SET催化域内的体细胞活化突变驱动肿瘤的侵袭性，耐药性和不良预后。在这里，我们报告了两个针对EZH2 Y641F和EZH2-EED相互作用的高通量筛选（HTS）运动。对于EZH2 Y641F突变体，HTS活动涉及使用均匀时间分辨荧光（HTRF）分析方法的250,000种化合物的库，并确定了162个匹配项，而60个匹配项通过荧光偏振（FP）分析筛选了160种化合物以防止EZH2-EED相互作用，产生97个结果。在162种EZH2 Y641F抑制剂中，有38种还抑制了EZH2-EED的相互作用，其中80种对宽型（WT）EZH2具有抑制作用。同时，在97种EZH2-EED相互作用抑制剂中，有10种对WT EZH2具有活性。这些命中化合物为开发针对其催化和非催化活性的新型PRC2-EZH2抑制剂提供了有用的工具。

更新日期：2020-05-11

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