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[1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-20 , DOI: 10.1016/j.ejmech.2019.111989 Zhong-Hua Li 1 , Jin-Lian Ma 1 , Gai-Zhi Liu 2 , Xin-Hui Zhang 3 , Ting-Ting Qin 1 , Wei-Hong Ren 4 , Tao-Qian Zhao 5 , Xiao-Hui Chen 1 , Zhen-Qiang Zhang 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2019-12-20 , DOI: 10.1016/j.ejmech.2019.111989 Zhong-Hua Li 1 , Jin-Lian Ma 1 , Gai-Zhi Liu 2 , Xin-Hui Zhang 3 , Ting-Ting Qin 1 , Wei-Hong Ren 4 , Tao-Qian Zhao 5 , Xiao-Hui Chen 1 , Zhen-Qiang Zhang 1
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Lysine specific demethylase 1 (LSD1) plays an essential role in maintaining a balanced methylation status at histone tails. Overexpression of LSD1 has been involved in the development of a variety of human diseases, including cancers. Herein, on the basis of our previously developed LSD1 inhibitors, two series of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety were designed and evaluated for their LSD1 inhibitory abilities, leading to a novel chemical class of LSD1 inhibitors. Among them, compound 31 was found to moderately inhibit LSD1 activity, as well as increase the expression of H3K4me2 at the cellular level. This compound also showed good selectivity against MAO-A/-B, and a panel of kinases such as CDK and BTK. Besides, the MTT assay suggested that the selected compounds could inhibit the proliferation of LSD1-overexpressed cancer cells. Although this class of compounds only showed moderate anti-LSD1 activity in the micromolar range, this work presents a novel chemotype of LSD1 inhibitors with good enzyme selectivity as well as cellular LSD1 inhibitory activity, and could provide a useful template for the development of more potent LSD1 inhibitors for cancer treatment.
中文翻译：
[1,2,3]三唑并[4,5-d]嘧啶衍生物并入（硫）脲部分作为LSD1抑制剂的新型支架。
赖氨酸特异性脱甲基酶1（LSD1）在维持组蛋白尾巴的平衡甲基化状态中起重要作用。LSD1的过表达已参与多种人类疾病的发展，包括癌症。在此，根据我们先前开发的LSD1抑制剂，设计了两个新的并入（硫代）脲部分的[1,2,3]三唑并[4,5-d]嘧啶衍生物系列，并评估了其对LSD1的抑制能力， LSD1抑制剂的新型化学类别。其中，发现化合物31适度抑制LSD1活性，并在细胞水平上增加H3K4me2的表达。该化合物还对MAO-A / -B和一系列激酶（例如CDK和BTK）表现出良好的选择性。除了，MTT分析表明所选择的化合物可以抑制LSD1过表达的癌细胞的增殖。尽管这类化合物仅在微摩尔范围内显示出适度的抗LSD1活性，但这项工作提出了具有良好酶选择性和细胞LSD1抑制活性的LSD1抑制剂的新型化学型，并可以为开发更有效的模板提供有用的模板。用于癌症治疗的LSD1抑制剂。
更新日期：2019-12-20
中文翻译：
[1,2,3]三唑并[4,5-d]嘧啶衍生物并入（硫）脲部分作为LSD1抑制剂的新型支架。
赖氨酸特异性脱甲基酶1（LSD1）在维持组蛋白尾巴的平衡甲基化状态中起重要作用。LSD1的过表达已参与多种人类疾病的发展，包括癌症。在此，根据我们先前开发的LSD1抑制剂，设计了两个新的并入（硫代）脲部分的[1,2,3]三唑并[4,5-d]嘧啶衍生物系列，并评估了其对LSD1的抑制能力， LSD1抑制剂的新型化学类别。其中，发现化合物31适度抑制LSD1活性，并在细胞水平上增加H3K4me2的表达。该化合物还对MAO-A / -B和一系列激酶（例如CDK和BTK）表现出良好的选择性。除了，MTT分析表明所选择的化合物可以抑制LSD1过表达的癌细胞的增殖。尽管这类化合物仅在微摩尔范围内显示出适度的抗LSD1活性，但这项工作提出了具有良好酶选择性和细胞LSD1抑制活性的LSD1抑制剂的新型化学型，并可以为开发更有效的模板提供有用的模板。用于癌症治疗的LSD1抑制剂。
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