Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

Abstract

<p>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 with a carboxamide at the 4-position of the aryl ring. These compounds, such as <b>5a</b> and <b>5b</b>, had potent submicromolar IC<sub>50</sub> values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The <i>t</i>-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.</p>