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

  • J Med Chem. 2016 Feb 25;59(4):1501-17. doi: 10.1021/acs.jmedchem.5b01209.
Paola Vianello  1 ,  Oronza A Botrugno  1 ,  Anna Cappa  1 ,  Roberto Dal Zuffo  1 ,  Paola Dessanti  1 ,  Antonello Mai  2  3 ,  Biagina Marrocco  2 ,  Andrea Mattevi  4 ,  Giuseppe Meroni  1 ,  Saverio Minucci  1  5 ,  Giulia Stazi  2 ,  Florian Thaler  1 ,  Paolo Trifiró  1 ,  Sergio Valente  2 ,  Manuela Villa  1 ,  Mario Varasi  1 ,  Ciro Mercurio  1  6
Affiliations
  • 1. Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
  • 2. Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.
  • 3. Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 4. Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
  • 5. Department of Biosciences, University of Milan , Via Celoria, 26, 20133 Milan, Italy.
  • 6. Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milan, Italy.
PMID: 26702542 DOI: 10.1021/acs.jmedchem.5b01209
Abstract

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.

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