title: 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.
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Schulz
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Junya
authors.initials: J
authors.lastname: Qu
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Erhard
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Mack
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Raha
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Szewczuk
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authors.forename: Patricia M
authors.initials: PM
authors.lastname: Kratz
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Jurewicz
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Ted
authors.initials: T
authors.lastname: Cecconie
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Martens
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McDevitt
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Martin
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Stephenie B
authors.initials: SB
authors.lastname: Chen
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authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
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authors.forename: Leng
authors.initials: L
authors.lastname: Nickels
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authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Schwartz
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authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
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authors.forename: Baoguang
authors.initials: B
authors.lastname: Zhao
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authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
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authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Qian
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authors.forename: Jacques
authors.initials: J
authors.lastname: Briand
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rominger
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authors.forename: Catherine
authors.initials: C
authors.lastname: Oleykowski
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.affiliation: Cancer Metabolism Chemistry; Cancer Metabolism Biology; and Platform Technology & Sciences, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426-0989, United States.
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
keywords: Hexokinase 2 inhibitor; crystal structure; structure−activity relationship selectivity