title: 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).
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.
authors.affiliation: Oncology Research, Novartis Institute for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07936-1080, USA. remisz@netscape.net
authors.forename: Stacy W
authors.initials: SW
authors.lastname: Remiszewski
authors.forename: Lidia C
authors.initials: LC
authors.lastname: Sambucetti
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Bair
authors.forename: John
authors.initials: J
authors.lastname: Bontempo
authors.forename: David
authors.initials: D
authors.lastname: Cesarz
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Chandramouli
authors.forename: Ru
authors.initials: R
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Cheung
authors.forename: Susan
authors.initials: S
authors.lastname: Cornell-Kennon
authors.forename: Karl
authors.initials: K
authors.lastname: Dean
authors.forename: George
authors.initials: G
authors.lastname: Diamantidis
authors.forename: Dennis
authors.initials: D
authors.lastname: France
authors.forename: Michael A
authors.initials: MA
authors.lastname: Green
authors.forename: Kobporn Lulu
authors.initials: KL
authors.lastname: Howell
authors.forename: Rina
authors.initials: R
authors.lastname: Kashi
authors.forename: Paul
authors.initials: P
authors.lastname: Kwon
authors.forename: Peter
authors.initials: P
authors.lastname: Lassota
authors.forename: Mary S
authors.initials: MS
authors.lastname: Martin
authors.forename: Yin
authors.initials: Y
authors.lastname: Mou
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Perez
authors.forename: Sushil
authors.initials: S
authors.lastname: Sharma
authors.forename: Troy
authors.initials: T
authors.lastname: Smith
authors.forename: Eric
authors.initials: E
authors.lastname: Sorensen
authors.forename: Francis
authors.initials: F
authors.lastname: Taplin
authors.forename: Nancy
authors.initials: N
authors.lastname: Trogani
authors.forename: Richard
authors.initials: R
authors.lastname: Versace
authors.forename: Heather
authors.initials: H
authors.lastname: Walker
authors.forename: Susan
authors.initials: S
authors.lastname: Weltchek-Engler
authors.forename: Alexander
authors.initials: A
authors.lastname: Wood
authors.forename: Arthur
authors.initials: A
authors.lastname: Wu
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000178:Acrylamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005260:Female; D051548:Histone Acetyltransferases; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D029701:Saccharomyces cerevisiae Proteins; D000123:Acetyltransferases; D051548:Histone Acetyltransferases