Open AccessDiscovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors
Author(s) -
Lin Hong,
Jin Zhang,
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 McDevitt,
John D. Martin,
Stephenie B. Chen,
Yong Mei Jiang,
Leng Nickels,
Benjamin J. Schwartz,
Angela Smallwood,
Baoguang Zhao,
Nino Campobasso,
Yanqiu Qian,
Jacques Briand,
Cynthia M. Rominger,
Catherine A. Oleykowski,
Mary Ann Hardwicke,
Juan I. Luengo
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.5b00214
Subject(s) - hexokinase , glycolysis , enzyme , chemistry , selectivity , glucosamine , cell culture , biochemistry , combinatorial chemistry , stereochemistry , biology , genetics , catalysis
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.