Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent

We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (<b>14a</b>–<b>k</b>, <b>15</b>, <b>16</b>), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (<b>14d</b>, <b>14e</b>, and <b>14g</b>) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. <b>14d</b> and <b>14e</b> were further tested in vivo in a murine acute promyelocytic leukemia model, resulting <b>14d</b> the most effective. Its two enantiomers were synthesized: the (1<i>S</i>,2<i>R</i>) enantiomer <b>15</b> showed higher activity than its (1<i>R</i>,2<i>S</i>) analogue <b>16</b>, in both biochemical and cellular assays. Compound <b>15</b> exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound <b>15</b> supports its further investigation as a cancer therapeutic