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 <b>1b>. 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>34b> with greater than 100-fold selectivity over HK1. Compound <b>25b> inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via 13CNMR measurement of [3-13C]lactate produced from [1,6-13Cb>2b>]glucose added to the cell culture.