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

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

  • ACS Med Chem Lett. 2015 Dec 28;7(3):217-22. doi: 10.1021/acsmedchemlett.5b00214.
Hong Lin 1,  Jin Zeng 1,  Ren Xie 1,  Mark J Schulz 1,  Rosanna Tedesco 1,  Junya Qu 1,  Karl F Erhard 1,  James F Mack 1,  Kaushik Raha 1,  Alan R Rendina 1,  Lawrence M Szewczuk 1,  Patricia M Kratz 1,  Anthony J Jurewicz 1,  Ted Cecconie 1,  Stan Martens 1,  Patrick J McDevitt 1,  John D Martin 1,  Stephenie B Chen 1,  Yong Jiang 1,  Leng Nickels 1,  Benjamin J Schwartz 1,  Angela Smallwood 1,  Baoguang Zhao 1,  Nino Campobasso 1,  Yanqiu Qian 1,  Jacques Briand 1,  Cynthia M Rominger 1,  Catherine Oleykowski 1,  Mary Ann Hardwicke 1,  Juan I Luengo 1
Affiliations

Affiliation

  • 1 Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
PMID: 26985301 DOI: 10.1021/acsmedchemlett.5b00214
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.

Keywords

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

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