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: IC50

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.