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)

• DOI: 10.1021/jm030235w
• Publication Date: 2003-10-02T04:28:23Z
• Authors: Stacy W. Remiszewski; Lidia C. Sambucetti; Kenneth W. Bair; John Bontempo; David Cesarz; Nagarajan Chandra...; 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-En...; Alexander Wood; Arthur Wu; Peter Atadja
• Keywords: Acrylamides; 0303 health sciences; Saccharomyces cerevisiae Proteins; Dose-Response Relationship, Drug; Body Weight; Molecular Conformation; Mice, Nude; Antineoplastic Agents; Hydroxamic Acids; 3. Good health; Mice; 03 medical and health sciences; Acetyltransferases; Drug Design; Animals; Humans; Female; Indicators and Reagents; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Cell Division; Neoplasm Transplantation; Histone Acetyltransferases

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.