发现一种新型组蛋白赖氨酸特异性去甲基化酶1A（KDM1A/LSD1）抑制剂作为口服活性抗肿瘤药物。
Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.
作者信息
Vianello Paola, Botrugno Oronza A, Cappa Anna, Dal Zuffo Roberto, Dessanti Paola, Mai Antonello, Marrocco Biagina, Mattevi Andrea, Meroni Giuseppe, Minucci Saverio, Stazi Giulia, Thaler Florian, Trifiró Paolo, Valente Sergio, Villa Manuela, Varasi Mario, Mercurio Ciro
机构信息
Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology , Via Adamello 16, 20139 Milan, Italy.
Department of Drug Chemistry and Technologies, Sapienza University of Rome , P.le A. Moro 5, 00185 Rome, Italy.
出版信息
J Med Chem. 2016 Feb 25;59(4):1501-17. doi: 10.1021/acs.jmedchem.5b01209. Epub 2016 Jan 7.
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.
我们报道了一系列新型反苯环丙胺（TCPA）衍生物（14a - k、15、16）的立体选择性合成及其生物活性，这些衍生物是KDM1A的强效抑制剂。新化合物强烈抑制急性白血病细胞系的克隆形成能力。特别是对三种对MAO A具有选择性且能显著抑制THP - 1人白血病细胞集落形成的分子（14d、14e和14g）进行了小鼠体内初步药代动力学评估。14d和14e在小鼠急性早幼粒细胞白血病模型中进行了进一步的体内试验，结果显示14d最为有效。合成了其两种对映体：在生化和细胞试验中，（1S,2R）对映体15的活性均高于其（1R,2S）类似物16。化合物15口服给药后显示出体内疗效，在小鼠白血病模型中使生存率提高了62%，且有KDM1A抑制的证据。化合物15的生物学特性支持其作为癌症治疗药物进行进一步研究。
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