Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors

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• 作者：Hong Lin ; Jin Zeng ; Ren Xie ; Mark J. Schulz ; Rosanna Tedesco ; Junya Qu ; Karl F. Erhard ; James F. Mack ; Kaushik Raha ; Alan R. Rendina ; Lawrence M. Szewczuk ; Patricia M. Kratz ; Anthony J. Jurewicz ; Ted Cecconie ; Stan Martens ; Patrick J. McDevitt ; John D. Martin ; Stephenie B. Chen ; Yong Jiang ; Leng Nickels ; Benjamin J. Schwartz ; Angela Smallwood ; Baoguang Zhao ; Nino Campobasso ; Yanqiu Qian ; Jacques Briand ; Cynthia M. Rominger ; Catherine Oleykowski ; Mary Ann Hardwicke ; Juan I. Luengo
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：217-222
• 全文大小：416K
• ISSN：1948-5875

文摘

A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an “induced-fit” conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via <sup>13sup>CNMR measurement of [3-<sup>13sup>C]lactate produced from [1,6-<sup>13sup>C<sub>2sub>]glucose added to the cell culture.