Discovery of [1,2,3]Triazolo[4,5-d]pyrimidine Derivatives as Novel LSD1 Inhibitors

作者：Li, Zhong-Hua; Liu, Xue-Qi; Geng, Peng-Fei; Suo, Feng-Zhi; Ma, Jin-Lian; Yu, Bin; Zhao, Tao-Qian; Zhou, Zhao-Qing; Huang, Chen-Xi; Zheng, Yi-Chao^*; Liu, Hong-Min^*

来源：ACS Medicinal Chemistry Letters, 2017, 8(4): 384-389.

DOI：10.1021/acsmedchemlett.6b00423

• [1,2,3]Triazolo[4,5-d]pyrimidine
• LSD1 inhibitor
• migration inhibition
• molecular docking

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 LSDI 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 mu M). Compound 27 was identified as a reversible LSDI inhibitor and showed certain selectivity to LSDI over monoamine oxidase A/B (MAO-A/B). When MGC-803 cells were treated with compound 27, the activity of LSDI 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.

• 出版日期2017-4
• 单位郑州大学