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

Abstract

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 IC₅₀ 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 IC₅₀ 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.