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

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 <b>1</b>. 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 <b>34</b> with greater than 100-fold selectivity over HK1. Compound <b>25</b> inhibits <i>in situ</i> glycolysis in a UM-UC-3 bladder tumor cell line via ¹³CNMR measurement of [3-¹³C]­lactate produced from [1,6-¹³C₂]­glucose added to the cell culture

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

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 <b>1</b>. 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 <b>34</b> with greater than 100-fold selectivity over HK1. Compound <b>25</b> inhibits <i>in situ</i> glycolysis in a UM-UC-3 bladder tumor cell line via ¹³CNMR measurement of [3-¹³C]­lactate produced from [1,6-¹³C₂]­glucose added to the cell culture