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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 / KDM1A inhibitors
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Synthesis, structure-activity relationship studies and biological characterization of new [1,2,4]triazolo[1,5-a]pyrimidine-based LSD1 / KDM1A inhibitors

机译：新的合成，结构 - 活性关系研究和新的新[1,2,4]三唑的LSD1 / KDM1A抑制剂的研/ KDM1A抑制剂

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The histone lysine specific demethylase 1 (LSD1/KDM1A) is implicated in the development of cancers, targeting LSD1 has been recognized as a promising strategy for cancer therapy. To date, some small molecule inhibitors are currently being investigated in clinical trials. Herein we report the design, synthesis and biochemical characterization of [1,2,4]triazolo[1,5-a]pyrimidine derivatives as new LSD1 inhibitors. Of these compounds, compound C26 inhibited LSD1 in a reversible manner (IC50 = 1.72 M) and showed selectivity to LSD1 over MAO-A/B. Besides, compound C26 displayed FAD-competitive binding to LSDI. Interestingly, C26 did not inhibit horseradish peroxidase (HRP) and quench H2O2, thus excluding the possibility that LSDI inhibition by C26 was due to the HRP inhibition and consumption of H2O2. In LSDI overexpressed A549 cells, compound C26 concentration-dependently induced accumulation of H3K4me1/me2 and H3K9me2 and showed cellular target engagement to LSD1. Additionally, compound C26 significantly inhibited migration of A549 cells in a concentration-dependent manner, further western blot analysis showed that C26 increased expression levels of epithelial cell markers E-Cadherin and Claudin-1, down-regulated mesenchymal cell marker N-Cadherin and the upstream transcription factors Snail and Slug. Docking studies were also performed to rationalize the potency of C26 toward LSD1. To conclude, the 11,2,41triazolo[1,5-a]pyrimidine could serve as a promising scaffold for the development of new LSD1 inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：组蛋白赖氨酸特异性去甲基酶1（LSD1 / KDM1A）涉及癌症的发育，靶向LSD1已被认为是癌症治疗的有希望的策略。迄今为止，目前正在在临床试验中研究一些小分子抑制剂。在此，我们报告了[1,2,4]三唑唑[1,5-A]嘧啶衍生物作为新的LSD1抑制剂的设计，合成和生化表征。在这些化合物中，化合物C26以可逆的方式（IC50 = 1.72m）抑制LSD1，并显示出对MAO-A / B的LSD1的选择性。此外，化合物C26显示了与LSDI的FAD竞争结合。有趣的是，C26没有抑制辣根过氧化物酶（HRP）和淬火H2O2，因此不包括C26的LSDI抑制的可能性是由于H2O2的HRP抑制和消耗。在LSDI过表达A549细胞中，化合物C26浓度依赖性诱导H3K4ME1 / ME2和H3K9ME2的积累，并显示对LSD1的细胞靶接合。另外，化合物C26以浓度依赖性方式显着抑制A549细胞的迁移，进一步的Western印迹分析表明，C26增加了上皮细胞标志物E-Cadherin和Claudin-1，下调的间充质细胞标记物N-Cadherin的表达水平。上游转录因子蜗牛和slug。还进行了对接研究以合理化C26对LSD1的效力。为了得出结论，11,2,41-1-1,5-A]嘧啶可以作为开发新的LSD1抑制剂的有前途的支架。 （c）2019年Elsevier Masson SAS。版权所有。

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