Journal of Medicinal Chemistry 2003-10-09

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).

Stacy W Remiszewski, 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

Index: J. Med. Chem. 46 , 4609-4624, (2003)

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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.