Discovery of novel tranylcypromine-indazole-based derivatives as LSD1 inhibitors for acute myeloid leukemia treatment.

As an epigenetic enzyme, Lysine-specific demethylase (LSD1) has emerged as a promising target for cancer therapy. Based on the structure of tranylcypromine indazole, a series of LSD1 inhibitors have been designed and synthesized in this work. Most compounds have excellent inhibitory activity against LSD1. The representative compound, 9e, proved to be a highly effective LSD1 inhibitor, with an IC value of 9.85 nM, and demonstrated exceptional selectivity for LSD1 over both MAOs and hERG. Meanwhile, compound 9e exhibited significant inhibitory activity against leukemia cells, especially MV-4-11, HL-60, and THP-1 cells, with IC values of 1.40, 1.54, and 1.96 μM respectively. Additional biological mechanisms suggested that compound 9e could directly target LSD1 and inhibit LSD1 in MV-4-11 cells, resulting in a significant increase in the expression levels of H3K4me1/2. In addition, compound 9e was found to induce apoptosis and upregulate of CD86-expression in MV-4-11 cells. All these findings indicated that compound 9e, a tranylcypromine-indazole derivative, provided a structural basis for LSD1 inhibitors in the treatment of acute myeloid leukemia.