Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

摘要: Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues carboxamide at the 4-position aryl ring. These compounds, such as 5 b benzyl phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for inhibition LSD1 well cell proliferation in panel AML lines. The dose-dependent increase cellular expression levels H3K4me2, CD86, CD11b CD14 supported mechanism involving inhibition. tert-butyl ethyl carbamate derivatives these tranylcypromines, although inactive inhibition, were similar potency cell-based assays more rapid onset action. This suggests that carbamates can act metabolically labile prodrugs superior pharmacokinetics.