Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors.
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Lin H, Zeng J, Xie R, Schulz MJ, Tedesco R, Qu J, Erhard KF, Mack JF, Raha K, Rendina AR, Szewczuk LM, Kratz PM, Jurewicz AJ, Cecconie T, Martens S, McDevitt PJ, Martin JD, Chen SB, Jiang Y, Nickels L, Schwartz BJ, Smallwood A, Zhao B, Campobasso N, Qian Y, Briand J, Rominger CM, Oleykowski C, Hardwicke MA, Luengo JI
Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors.
ACS Med Chem Lett. 2015 Dec 28;7(3):217-22. doi: 10.1021/acsmedchemlett.5b00214. eCollection 2016 Mar 10.
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- 26985301 [ View in PubMed]
- Abstract
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 (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.