European Journal of Medicinal Chemistry p. 357 - 372 (2019)
Update date:2022-08-03
Topics:
Liu, Hong-Min
Suo, Feng-Zhi
Li, Xiao-Bo
You, Ying-Hua
Lv, Chun-Tao
Zheng, Chen-Xing
Zhang, Guo-Chen
Liu, Yue-Jiao
Kang, Wen-Ting
Zheng, Yi-Chao
Xu, Hai-Wei
Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 μM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.
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