Discovery of higenamine as a potent, selective and cellular active natural LSD1 inhibitor for MLL-rearranged leukemia therapy.

Natural products are a rich source of lead compounds and have shown promise for epigenetic drug discovery. In this work, we discovered higenamine from our natural product library as a potent, selective and cellular active natural LSD1 inhibitor. Higenamine shows acceptable potency against LSD1 and high selectivity towards LSD1 over MAOA/B. Higenamine significantly increases expression of LSD1 substrates H3K4me1 and H3K4me2 in MLL-rearranged leukemia cells MV4-11 and MOLM-13, but nearly had no effect on LSD1 and H3K4Me3. Meanwhile, higenamine dose-dependently suppresses the levels of HOXA9 and MEIS1 that are overexpressed in leukemia cell lines. Notably, higenamine induces cell differentiation of MV4-11 and MOLM-13 cells accompanying by increased expression of CD11b, CD14 and CD86. Higenamine promotes cell apoptosis, inhibits colony formation, but does not inhibit proliferation of leukemia cells significantly. In addition, the expression levels of p53 are dramatically changed by higenamine in an LSD1-dependent manner in MV4-11 cells. Taken together, higenamine could be employed as a starting point for the development of more selective and potent LSD1 inhibitors. Our work firstly reveals the non-classical epigenetic regulation mechanism of higenamine in cancers, and also demonstrates the efficacy of higenamine for MLL-rearranged leukemia therapy.