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Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.
- Source :
-
Journal of Medicinal Chemistry . Feb2016, Vol. 59 Issue 4, p1501-1517. 17p. - Publication Year :
- 2016
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 59
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 113570845
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b01209