N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity:  Discovery of (2E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824)

IC50
DOI: 10.1021/jm030235w Publication Date: 2003-10-02T04:28:23Z
ABSTRACT
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors human histone deacetylase (HDAC). These compounds potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified assay. However, potency cell growth inhibition assays ranged over 2 orders magnitude two carcinoma lines. Selected cellular IC(50) 750 tested for maximum tolerated dose (MTD) and efficacy the HCT116 colon tumor xenograft Four an MTD > or = 100 mg/kg selected dose-response studies model. One compound, 9 (NVP-LAQ824), had significant dose-related activity A549 lung models, high MTD, low gross toxicity. On basis, part, these properties, has entered clinical trials 2002.
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