Natural protoberberine alkaloids, identified as potent selective LSD1 inhibitors, induce AML cell differentiation

• Published in: Bioorganic chemistry 2020-04, Vol.97, p.103648-103648, Article 103648
• Main Authors: Li, Zhong-Rui, Suo, Feng-Zhi, Guo, Yan-Jia, Cheng, Hai-Fang, Niu, Sheng-Hui, Shen, Dan-Dan, Zhao, Li-Juan, Liu, Zhen-Zhen, MAA, Mamun, Yu, Bin, Zheng, Yi-Chao, Liu, Hong-Min
• Format: Article
• Language: English
• Subjects: AML treatment; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Berberine Alkaloids - pharmacology; Berberine Alkaloids - therapeutic use; Cell Differentiation - drug effects; Cell Survival - drug effects; Epiberberine; Female; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - metabolism; HL-60 Cells; Humans; Leukemia, Myeloid, Acute - drug therapy; LSD1 inhibitors; Mice; Mice, SCID; Natural protoberberine alkaloids
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103648

[Display omitted] •It is the first time to report tetracyclic protoberberine alkaloids as LSD1 inhibitors.•Epiberberine could inactive LSD1 in AML cell lines.•Epiberberine induces differentiation of AML cell lines.•Epiberberine prolongs survival of mice bearing THP-1 cells. Natural protoberberine alkaloids were first identified and characterized as potent, selective and cellular active lysine specific demethylase 1 (LSD1) inhibitors. Due to our study, isoquinoline-based tetracyclic scaffold was identified as the key structural element for their anti-LSD1 activity, subtle changes of substituents attached to the core structure led to dramatic changes of the activity. Among these protoberberine alkaloids, epiberberine potently inhibited LSD1 (IC50 = 0.14 ± 0.01 μM) and was highly selective to LSD1 over MAO-A/B. Furthermore, epiberberine could induce the expression of CD86, CD11b and CD14 in THP-1 and HL-60 cells, confirming its cellular activity of inducing acute myeloid leukemia (AML) cells differentiation. Moreover, epiberberine prolonged the survival of THP-1 cells bearing mice and inhibited the growth of AML cells in vivo without obvious global toxicity. These findings give the potential application of epiberberine in AML treatment, and the isoquinoline-based tetracyclic scaffold could be used for further development of LSD1 inhibitors.