Journal Article
Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent
Vianello, P; Botrugno, OA; Cappa, A; Dal Zuffo, R; Dessanti, P; Mai, A; Marrocco, B; Mattevi, A; Meroni, G; Minucci, S; Stazi, G; Thaler, F; Trifirã³, P; Valente, S; Villa, M; Varasi, M; Mercurio, C
Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804
American Chemical Society
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. © 2015 American Chemical Society.
(trans) 2 (4 iodophenyl)cyclopropanecarboxylic acid; 1 ethyl 2 phenylcyclopropanecarboxylate; 2 (4 iodophenyl)cyclopropanecarboxylic acid; 2 phenylcyclopropanecarboxylic acid; 3 (2 oxooxazolidin 3 yl)benzamide; 4 (1 methyl 4 piperidyl)benzamide; 4 (2 oxooxazolidin 3 yl)benzamide; antineoplastic agent; benzyl n [3 [[4 (trans 2 aminocyclopropyl)phenyl] carbamoyl]phenyl]carbamate; n [4 [2 aminocyclopropyl]phenyl] 4 (4 methylpiperazin 1 yl)benzamide; n [4 [trans 2 aminocyclopropyl]phenyl] 3 (2 oxooxazolidin 3 yl)benzamide; n [4 [trans 2 aminocyclopropyl]phenyl] 4 (1 methyl 4 piperidyl)benzamide trifluoroacetate; n [4 [trans 2 aminocyclopropyl]phenyl] 4 (2 oxooxazolidin 3 yl)benzamide trifluoroacetate; n [4 [trans 2 aminocyclopropyl]phenyl] 4 (3 furyl) benzamide; n [4 [trans 2 aminocyclopropyl]phenyl] 4 (4 methylpiperazin 1 yl)benzamide; tert butyl 3 (benzyloxycarbonylamino) 4 (4 methylpiperazin 1 yl)benzoate; tert butyl 3 amino 4 (4 methylpiperazin 1 yl)benzoate; tert butyl 3 morpholino 4 (benzyloxycarbonylamino) benzoate; tert butyl 3 morpholino 4 aminobenzoate; tert butyl 3 morpholino 4 nitrobenzoate; tert butyl 4 (1 piperidyl) 3 aminobenzoate; tert butyl 4 (1 piperidyl) 3 nitrobenzoate; tert butyl 4 (4 methylpiperazin 1 yl) 3 nitrobenzoate; tert butyl 4 morpholino 3 (benzyloxycarbonylamino) benzoate; tert butyl 4 morpholino 3 aminobenzoate; tert butyl 4 morpholino 3 nitrobenzoate; tert butyl n [2 (4 iodophenyl)cyclopropyl] carbamate; tert butyl n [trans 2 (4 iodophenyl)cyclopropyl]carbamate; tranylcypromine derivative; unclassified drug; unindexed drug; antineoplastic agent; enzyme inhibitor; histone demethylase; KDM1A protein, human; tranylcypromine; acute leukemia; animal experiment; animal model; antineoplastic activity; area under the curve; Article; colony formation; colony forming unit; down regulation; drug bioavailability; drug clearance; drug efficacy; drug half life; drug synthesis; enantiomer; human; human cell; IC50; in vitro study; in vivo study; leukemia cell line; maximum plasma concentration; mouse; murine leukemia; nonhuman; promyelocytic leukemia; racemic mixture; structure activity relation; time to maximum plasma concentration; volume of distribution; antagonists and inhibitors; chemistry; Leukemia, Promyelocytic, Acute; metabolism; oral drug administration; tumor cell line; Administration, Oral; Antineoplastic Agents; Cell Line, Tumor; Enzyme Inhibitors; Histone Demethylases; Humans; Leukemia, Promyelocytic, Acute; Structure-Activity Relationship; Tranylcypromine