title: Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.
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.
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Oronza A
authors.initials: OA
authors.lastname: Botrugno
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Dal Zuffo
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Dessanti
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.|Pasteur Institute-Cenci Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.affiliation: Department of Biology and Biotechnology, University of Pavia , Via Ferrata 1, 27100 Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Meroni
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.|Department of Biosciences, University of Milan , Via Celoria, 26, 20133 Milan, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Stazi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Trifiró
authors.affiliation: Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Villa
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.|Genextra Group, DAC s.r.l. , Via Adamello 16, 20139 Milan, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human