Discovery of novel tranylcypromine-based derivatives as LSD1 inhibitors for gastric cancer treatment

As an important epigenetic regulator, histone lysine specific demethylase 1 (LSD1) has become an attractive target for the discovery of anticancer agents. In this work, a series of tranylcypromine-based derivatives were designed and synthesized. Among them, compound 12u exhibited the most potent inhibitory potency on LSD1 (IC50 = 25.3 nM), and also displayed good antiproliferative effects on MGC-803, KYSE450 and HCT-116 cells with IC50 values of 14.3, 22.8 and 16.3 mu M, respectively. Further studies revealed that compound 12u could directly act on LSD1 and inhibit LSD1 in MGC-803 cells, thereby significantly increasing the expression levels of mono-/bi-methylation of H3K4 and H3K9. In addition, compound 12u could induce apoptosis and differentia-tion, inhibit migration and cell stemness in MGC-803 cells. All these findings suggested that compound 12u was an active tranylcypromine-based derivative as a LSD1 inhibitor that inhibited gastric cancer.

Automated summary

Histone lysine specific demethylase 1 (LSD1), an important epigenetic regulator, is a promising target for anticancer drug discovery. This study designed and synthesized a series of tranylcypromine-based derivatives, among which compound 12u exhibited the most potent inhibitory potency on LSD1 and showed effective antiproliferative effects on MGC-803, KYSE450, and HCT-116 cells. Further investigations demonstrated that compound 12u directly targeted LSD1, leading to increased levels of mono-/bi-methylation of H3K4 and H3K9. Additionally, compound 12u induced apoptosis, differentiation, and inhibition of migration and cell stemness in MGC-803 cells, suggesting its potential as an active LSD1 inhibitor for gastric cancer.