Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

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• 作者：Brian K. Albrecht ; Victor S. Gehling ; Michael C. Hewitt ; Rishi G. Vaswani ; Alexandre Côté ; Yves Leblanc ; Christopher G. Nasveschuk ; Steve Bellon ; Louise Bergeron ; Robert Campbell ; Nico Cantone ; Michael R. Cooper ; Richard T. Cummings ; Hariharan Jayaram ; Shivangi Joshi ; Jennifer A. Mertz ; Adrianne Neiss ; Emmanuel Normant ; Michael O’Meara ; Eneida Pardo ; Florence Poy ; Peter Sandy ; Jeffrey Supko ; Robert J. Sims III ; Jean-Christophe Harmange ; Alexander M. Taylor ; James E. Audia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1330-1339
• 全文大小：651K
• ISSN：1520-4804

文摘

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610).