2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2003 Oct 9;46(21):4609-24. doi: 10.1021/jm030235w.
Stacy W Remiszewski 1,  Lidia C Sambucetti,  Kenneth W Bair,  John Bontempo,  David Cesarz,  Nagarajan Chandramouli,  Ru Chen,  Min Cheung,  Susan Cornell-Kennon,  Karl Dean,  George Diamantidis,  Dennis France,  Michael A Green,  Kobporn Lulu Howell,  Rina Kashi,  Paul Kwon,  Peter Lassota,  Mary S Martin,  Yin Mou,  Lawrence B Perez,  Sushil Sharma,  Troy Smith,  Eric Sorensen,  Francis Taplin,  Nancy Trogani,  Richard Versace,  Heather Walker,  Susan Weltchek-Engler,  Alexander Wood,  Arthur Wu,  Peter Atadja
Affiliations

Affiliation

  • 1 Oncology Research, Novartis Institute for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07936-1080, USA. remisz@netscape.net
PMID: 14521422 DOI: 10.1021/jm030235w
Abstract

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

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