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

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.

SUBMITTER: Lin H

PROVIDER: S-EPMC4789681 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Lin Hong H Zeng Jin J Xie Ren R Schulz Mark J MJ Tedesco Rosanna R Qu Junya J Erhard Karl F KF Mack James F JF Raha Kaushik K Rendina Alan R AR Szewczuk Lawrence M LM Kratz Patricia M PM Jurewicz Anthony J AJ Cecconie Ted T Martens Stan S McDevitt Patrick J PJ Martin John D JD Chen Stephenie B SB Jiang Yong Y Nickels Leng L Schwartz Benjamin J BJ Smallwood Angela A Zhao Baoguang B Campobasso Nino N Qian Yanqiu Y Briand Jacques J Rominger Cynthia M CM Oleykowski Catherine C Hardwicke Mary Ann MA Luengo Juan I JI

ACS medicinal chemistry letters 20151228 3

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 ...[more]

PMID: 26985301

Dataset Information

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

Publications

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

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