Lysine specific demethylase 1 (LSD1) plays a pivotal role in regulating the lysine methylation. The aberrant overexpression of LSD1 has been reported to be involved in the progression of certain human malignant tumors. Abrogation of LSD1 with RNAi or small molecule inhibitors may lead to the inhibition of cancer proliferation and migration. Herein, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives were synthesized and evaluated for their LSD1 inhibitory effects. The structure-activity relationship studies (SARs) were conducted by exploring three regions of this scaffold, leading to the discovery of compound 27 as potent LSD1 inhibitor (IC50 = 0.564 μM). Compound 27 was identified as a reversible LSD1 inhibitor and showed certain selectivity to LSD1 over monoamine oxidase A/B (MAO-A/B). When MGC-803 cells were treated with compound 27, the activity of LSD1 can be significantly inhibited, and the cell migration ability was also suppressed. Docking studies indicated that the hydrogen interaction between the nitrogen atom in the pyridine ring and Met332 could be responsible for the improved activity of 2-thiopyridine series. The [1,2,3]triazolo[4,5-d]pyrimidine scaffold can be used as the template for designing new LSD1 inhibitors.

中文翻译：

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发现[1,2,3]三唑并[4,5-d]嘧啶衍生物作为新型LSD1抑制剂。

赖氨酸特异性脱甲基酶1（LSD1）在调节赖氨酸甲基化中起关键作用。据报道，LSD1的异常过度表达与某些人类恶性肿瘤的进展有关。用RNAi或小分子抑制剂替代LSD1可能导致抑制癌症的增殖和迁移。在此，合成了一系列的[1,2,3]三唑并[4,5-d]嘧啶衍生物，并评价了其对LSD1的抑制作用。通过探索该支架的三个区域进行了结构活性关系研究（SAR），从而发现了化合物27作为有效的LSD1抑制剂（IC50 = 0.564μM）。化合物27被鉴定为可逆LSD1抑制剂，相对于单胺氧化酶A / B（MAO-A / B）对LSD1具有一定的选择性。用化合物27处理MGC-803细胞时，LSD1的活性可以被显着抑制，并且细胞迁移能力也被抑制。对接研究表明，吡啶环中氮原子与Met332之间的氢相互作用可能是2-硫代吡啶系列活性提高的原因。[1,2,3]三唑并[4,5-d]嘧啶骨架可以用作设计新型LSD1抑制剂的模板。