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 (14a–k, 15, 16), potent
inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic
potential of acute leukemia cell lines. In particular three molecules
(14d, 14e, and 14g) showing
selectivity versus MAO A and remarkably inhibiting colony formation
in THP-1 human leukemia cells, were assessed in mouse for their preliminary
pharmacokinetic. 14d and 14e were further
tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized:
the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays.
Compound 15 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 15 supports its further investigation as a cancer therapeutic.