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).
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.
Remiszewski
Stacy W
SW
Oncology Research, Novartis Institute for Biomedical Research, 1 Health Plaza, East Hanover, NJ 07936-1080, USA. remisz@netscape.net
Sambucetti
Lidia C
LC
Bair
Kenneth W
KW
Bontempo
John
J
Cesarz
David
D
Chandramouli
Nagarajan
N
Chen
Ru
R
Cheung
Min
M
Cornell-Kennon
Susan
S
Dean
Karl
K
Diamantidis
George
G
France
Dennis
D
Green
Michael A
MA
Howell
Kobporn Lulu
KL
Kashi
Rina
R
Kwon
Paul
P
Lassota
Peter
P
Martin
Mary S
MS
Mou
Yin
Y
Perez
Lawrence B
LB
Sharma
Sushil
S
Smith
Troy
T
Sorensen
Eric
E
Taplin
Francis
F
Trogani
Nancy
N
Versace
Richard
R
Walker
Heather
H
Weltchek-Engler
Susan
S
Wood
Alexander
A
Wu
Arthur
A
Atadja
Peter
P
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*
D000178:Acrylamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D029701:Saccharomyces cerevisiae Proteins; D000123:Acetyltransferases; D051548:Histone Acetyltransferases