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首页> 美国卫生研究院文献>Molecules >Identification and Characterizations of Novel Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search
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Identification and Characterizations of Novel Selective Histone Methyltransferase SET7 Inhibitors by Scaffold Hopping- and 2D-Molecular Fingerprint-Based Similarity Search

机译：新型的选择性的组蛋白甲基转移酶SET7抑制剂的识别和表征通过基于支架跳跃和2D分子指纹的相似性搜索

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摘要

SET7, serving as the only histone methyltransferase that monomethylates ‘Lys-4’ of histone H3, has been proved to function as a key regulator in diverse biological processes, such as cell proliferation, transcriptional network regulation in embryonic stem cell, cell cycle control, protein stability, heart morphogenesis and development. What′s more, SET7 is involved inthe pathogenesis of alopecia aerate, breast cancer, tumor and cancer progression, atherosclerosis in human carotid plaques, chronic renal diseases, diabetes, obesity, ovarian cancer, prostate cancer, hepatocellular carcinoma, and pulmonary fibrosis. Therefore, there is urgent need to develop novel SET7 inhibitors. In this paper, based on DC-S239 which has been previously reported in our group, we employed scaffold hopping- and 2D fingerprint-based similarity searches and identified DC-S285 as the new hit compound targeting SET7 (IC50 = 9.3 μM). Both radioactive tracing and NMR experiments validated the interactions between DC-S285 and SET7 followed by the second-round similarity search leading to the identification ofDC-S303 with the IC50 value of 1.1 μM. In cellular level, DC-S285 retarded tumor cell proliferation and showed selectivity against MCF7 (IC50 = 21.4 μM), Jurkat (IC50 = 2.2 μM), THP1 (IC50 = 3.5 μM), U937 (IC50 = 3.9 μM) cell lines. Docking calculations suggested that DC-S303 share similar binding mode with the parent compoundDC-S239. What′s more, it presented good selectivity against other epigenetic targets, including SETD1B, SETD8, G9a, SMYD2 and EZH2. DC-S303 can serve as a drug-like scaffold which may need further optimization for drug development, and can be used as chemical probe to help the community to better understand the SET7 biology.
机译：SET7是唯一使组蛋白H3的“ Lys-4”单甲基化的组蛋白甲基转移酶，已被证明在多种生物学过程中起着关键的调节作用，例如细胞增殖，胚胎干细胞的转录网络调控，细胞周期控制，蛋白质稳定，心脏形态发生和发展。此外，SET7参与了以下疾病的发病机理：斑秃，乳腺癌，肿瘤和癌症进展，人颈动脉斑块的动脉粥样硬化，慢性肾脏疾病，糖尿病，肥胖症，卵巢癌，前列腺癌，肝细胞癌和肺纤维化。因此，迫切需要开发新型的SET7抑制剂。在本文中，基于我们小组先前已报道的DC-S239，我们采用基于支架跳跃和2D指纹的相似性搜索，并将DC-S285确定为靶向SET7的新型命中化合物（IC50 = 9.3μM）。放射性示踪和NMR实验均验证了DC-S285与SET7之间的相互作用，随后进行了第二轮相似性搜索，从而鉴定出IC-值为1.1μM的DC-S303。在细胞水平上，DC-S285抑制肿瘤细胞增殖并显示出对MCF7（IC50 = 21.4μM），Jurkat（IC50 = 2.2μM），THP1（IC50 = 3.5μM），U937（IC50 = 3.9μM）细胞系的选择性。对接计算表明DC-S303与母体化合物DC-S239共享相似的绑定模式。而且，它对其他表观遗传靶标（包括SETD1B，SETD8，G9a，SMYD2和EZH2）具有良好的选择性。 DC-S303可以用作类药物支架，可能需要进一步优化以开发药物，并且可以用作化学探针，以帮助社区更好地了解SET7生物学。

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