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ACS Med Chem Lett. 2015 Dec 28;7(3):217-22. doi: 10.1021/acsmedchemlett.5b00214. eCollection 2016 Mar 10.

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

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Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.


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.


Hexokinase 2 inhibitor; crystal structure; structure−activity relationship selectivity

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