Design and optimization of selective and potent LSD1 inhibitors with tranylcypromine-pyrimidine scaffold for the treatment of acute myeloid leukemia.

Lysine-specific demethylase 1 (LSD1), a key epigenetic regulator mediating histone modification, has been a potential therapeutic target for acute myeloid leukemia (AML) due to its critical role in disease pathogenesis. In this work, we designed and synthesized novel LSD1 inhibitors with the scaffold of tranylcypromine-pyrimidine. The representative compound 7a was a highly effective LSD1 inhibitor (IC50 = 7.87 nM) with excellent selectivity over MAO-A and MAO-B (>127-fold over MAO-A and > 1270-fold over MAO-B). Meanwhile, compound 7a also showed effective inhibitory activity against MV-4-11 with IC50 values of 0.36 μM. Mechanistic studies demonstrated that 7a could directly targeted LSD1, thereby promoting a significant increase of H3K4me1/2 histone methylation levels in MV-4-11 cells. 7a induced apoptosis while upregulating the differentiation marker CD86 and downregulating the stem cell-associated proteins SOX2 and CD44. Collectively, these findings establish compound 7a, a tranylcypromine-pyrimidine derivative, provides the structural foundation for the development of LSD1 inhibitors for the treatment of AML.