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

被引：67

作者：

Lin, Hong ^{[1
]}

Zeng, Jin ^{[1
]}

Xie, Ren ^{[1
]}

Schulz, Mark J. ^{[1
]}

Tedesco, Rosanna ^{[1
]}

Qu, Junya ^{[1
]}

Erhard, Karl F. ^{[1
]}

Mack, James F. ^{[1
]}

Raha, Kaushik ^{[3
]}

Rendina, Alan R. ^{[3
]}

Szewczuk, Lawrence M. ^{[3
]}

Kratz, Patricia M. ^{[3
]}

Jurewicz, Anthony J. ^{[3
]}

Cecconie, Ted ^{[3
]}

Martens, Stan ^{[3
]}

McDevit, Patrick J. ^{[3
]}

Martin, John D. ^{[3
]}

Chen, Stephenie B. ^{[3
]}

Jiang, Yong ^{[3
]}

Nickels, Leng ^{[3
]}

Schwartz, Benjamin J. ^{[3
]}

Smallwood, Angela ^{[3
]}

Zhao, Baoguang ^{[3
]}

Campobasso, Nino ^{[3
]}

Qian, Yanqiu ^{[3
]}

Briand, Jacques ^{[3
]}

Rominger, Cynthia M. ^{[2
]}

Oleykowski, Catherine ^{[2
]}

Hardwicke, Mary Ann ^{[2
]}

Luengo, Juan I. ^{[1
]}

机构：

[1] GlaxoSmithKline, Canc Metab Chem, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

[2] GlaxoSmithKline, Canc Metab Biol, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

[3] GlaxoSmithKline, Platform Technol & Sci, 1250 South Collegeville Rd, Collegeville, PA 19426 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 03期

关键词：

Hexokinase; 2; inhibitor; crystal structure; structure-activity relationship selectivity; II HEXOKINASE; CANCER; GROWTH;

D O I：

10.1021/acsmedchemlett.5b00214

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (CNMR)-C-13 measurement of [3-C-13]lactate produced from [1,6-C-13(2)]glucose added to the cell culture.

引用

页码：217 / 222

页数：6

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