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
  • 1. Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
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.