CZ415, a Highly Selective mTOR Inhibitor Showing in Vivo Efficacy in a Collagen Induced Arthritis Model

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• 作者：Andrew D. Cansfield ; Tammy Ladduwahetty ; Mihiro Sunose ; Katie Ellard ; Rosemary Lynch ; Anthea L. Newton ; Ann Lewis ; Gavin Bennett ; Nico Zinn ; Douglas W. Thomson ; Anne J. Rüger ; John T. Feutrill ; Oliver Rausch ; Alan P. Watt ; Giovanna Bergamini
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：7
• 期：8
• 页码：768-773
• 全文大小：380K
• 年卷期：0
• ISSN：1948-5875

文摘

CZ415, a potent ATP-competitive mTOR inhibitor with unprecedented selectivity over any other kinase is described. In addition to a comprehensive characterization of its activities in vitro, in vitro ADME, and in vivo pharmacokinetic data are reported. The suitability of this inhibitor for studying in vivo mTOR biology is demonstrated in a mechanistic mouse model monitoring mTOR proximal downstream phosphorylation signaling. Furthermore, the compound reported here is the first ATP-competitive mTOR inhibitor described to show efficacy in a semitherapeutic collagen induced arthritis (CIA) mouse model.