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
  • 1. Oncology Research, Novartis Institute for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07936-1080, USA. [email protected]
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.