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

Paola Vianello, Oronza A. Botrugno, Anna Cappa, Roberto Dal Zuffo, Paola Dessanti, Antonello Mai, Biagina Marrocco, Andrea Mattevi, Giuseppe Meroni, Saverio Minucci, Giulia Stazi, Florian Thaler, Paolo Trifiró, Sergio Valente, Manuela Villa, Mario Varasi, Ciro Mercurio

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1501-1517
Number of pages17
JournalJournal of Medicinal Chemistry
Issue number4
Publication statusPublished - Feb 25 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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