Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

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 13CNMR measurement of [3-13C]lactate produced from [1,6-13C2]glucose added to the cell culture.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [2] more »;  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [3];  [3];  [1] « less
+ Show Author Affiliations
  1. GlaxoSmithKline, Collegeville, PA (United States). Cancer Metabolism Chemistry
  2. GlaxoSmithKline, Collegeville, PA (United States). Platform Technology and Sciences
  3. GlaxoSmithKline, Collegeville, PA (United States). Cancer Metabolism Biology
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1438892
Resource Type:
Accepted Manuscript
Journal Name:
ACS Medicinal Chemistry Letters
Additional Journal Information:
Journal Volume: 7; Journal Issue: 3; Journal ID: ISSN 1948-5875
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Amides; Peptides and proteins; Carbohydrates; Inhibitors; Inhibition; Hexokinase 2 inhibitor; crystal structure; structure−activity relationship selectivity

Citation Formats

Lin, Hong, Zeng, Jin, Xie, Ren, Schulz, Mark J., Tedesco, Rosanna, Qu, Junya, Erhard, Karl F., Mack, James F., Raha, Kaushik, Rendina, Alan R., Szewczuk, Lawrence M., Kratz, Patricia M., Jurewicz, Anthony J., Cecconie, Ted, Martens, Stan, McDevitt, Patrick J., Martin, John D., Chen, Stephenie B., Jiang, Yong, Nickels, Leng, Schwartz, Benjamin J., Smallwood, Angela, Zhao, Baoguang, Campobasso, Nino, Qian, Yanqiu, Briand, Jacques, Rominger, Cynthia M., Oleykowski, Catherine, Hardwicke, Mary Ann, and Luengo, Juan I. Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors. United States: N. p., 2015. Web. doi:10.1021/acsmedchemlett.5b00214.
Copy to clipboard
Lin, Hong, Zeng, Jin, Xie, Ren, Schulz, Mark J., Tedesco, Rosanna, Qu, Junya, Erhard, Karl F., Mack, James F., Raha, Kaushik, Rendina, Alan R., Szewczuk, Lawrence M., Kratz, Patricia M., Jurewicz, Anthony J., Cecconie, Ted, Martens, Stan, McDevitt, Patrick J., Martin, John D., Chen, Stephenie B., Jiang, Yong, Nickels, Leng, Schwartz, Benjamin J., Smallwood, Angela, Zhao, Baoguang, Campobasso, Nino, Qian, Yanqiu, Briand, Jacques, Rominger, Cynthia M., Oleykowski, Catherine, Hardwicke, Mary Ann, & Luengo, Juan I. Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors. United States. https://doi.org/10.1021/acsmedchemlett.5b00214
Copy to clipboard
Lin, Hong, Zeng, Jin, Xie, Ren, Schulz, Mark J., Tedesco, Rosanna, Qu, Junya, Erhard, Karl F., Mack, James F., Raha, Kaushik, Rendina, Alan R., Szewczuk, Lawrence M., Kratz, Patricia M., Jurewicz, Anthony J., Cecconie, Ted, Martens, Stan, McDevitt, Patrick J., Martin, John D., Chen, Stephenie B., Jiang, Yong, Nickels, Leng, Schwartz, Benjamin J., Smallwood, Angela, Zhao, Baoguang, Campobasso, Nino, Qian, Yanqiu, Briand, Jacques, Rominger, Cynthia M., Oleykowski, Catherine, Hardwicke, Mary Ann, and Luengo, Juan I. Mon . "Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors". United States. https://doi.org/10.1021/acsmedchemlett.5b00214. https://www.osti.gov/servlets/purl/1438892.
Copy to clipboard
@article{osti_1438892,
title = {Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors},
author = {Lin, Hong and Zeng, Jin and Xie, Ren and Schulz, Mark J. and Tedesco, Rosanna and Qu, Junya and Erhard, Karl F. and Mack, James F. and Raha, Kaushik and Rendina, Alan R. and Szewczuk, Lawrence M. and Kratz, Patricia M. and Jurewicz, Anthony J. and Cecconie, Ted and Martens, Stan and McDevitt, Patrick J. and Martin, John D. and Chen, Stephenie B. and Jiang, Yong and Nickels, Leng and Schwartz, Benjamin J. and Smallwood, Angela and Zhao, Baoguang and Campobasso, Nino and Qian, Yanqiu and Briand, Jacques and Rominger, Cynthia M. and Oleykowski, Catherine and Hardwicke, Mary Ann and Luengo, Juan I.},
abstractNote = {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 13CNMR measurement of [3-13C]lactate produced from [1,6-13C2]glucose added to the cell culture.},
doi = {10.1021/acsmedchemlett.5b00214},
journal = {ACS Medicinal Chemistry Letters},
number = 3,
volume = 7,
place = {United States},
year = {Mon Dec 28 00:00:00 EST 2015},
month = {Mon Dec 28 00:00:00 EST 2015}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acsmedchemlett.5b00214
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 53 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: (A) Compound 1 in HK2 with G6P overlaid with 2NZT; (B) Compound 1 and G6P interactions with HK2 in the C-terminal catalytic pocket.
All figures and tables (6 total)
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

Glycolysis inhibition for anticancer treatment
journal, August 2006

Hexokinase-2 bound to mitochondria: Cancer's stygian link to the “Warburg effect” and a pivotal target for effective therapy
journal, February 2009

Aberrant Glycolytic Metabolism of Cancer Cells: A Remarkable Coordination of Genetic, Transcriptional, Post-translational, and Mutational Events That Lead to a Critical Role for Type II Hexokinase
journal, August 1997

  • Mathupala, Saroj P.; Rempel, Annette; Pedersen, Peter L.
  • Journal of Bioenergetics and Biomembranes, Vol. 29, Issue 4, p. 339-343
  • DOI: 10.1023/A:1022494613613

Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention
journal, September 2002

  • Pedersen, Peter L.; Mathupala, Saroj; Rempel, Annette
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1555, Issue 1-3
  • DOI: 10.1016/S0005-2728(02)00248-7

Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines
journal, August 2009

  • Ahn, Keun Jae; Hwang, Hee Sung; Park, Jeon Han
  • Journal of Nuclear Medicine, Vol. 50, Issue 9
  • DOI: 10.2967/jnumed.108.060780

Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo
journal, July 2008

  • Peng, Qiuping; Zhou, Qi; Zhong, Daping
  • Cancer Biology & Therapy, Vol. 7, Issue 7
  • DOI: 10.4161/cbt.7.7.6199

Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer
journal, August 2013

The structure of mammalian hexokinase-1
journal, July 1998

  • Mulichak, Anne M.; Wilson, John E.; Padmanabhan, Kaillathe
  • Nature Structural Biology, Vol. 5, Issue 7
  • DOI: 10.1038/811

A convenient preparation of some 2,3,4,6-tetra-O-acetyl-1,5-anhydro-d-hexitols
journal, December 1982

Crystal structure of human hexokinase II
journal, December 2006

  • Rabeh, W. M.; Zhu, H.; Nedyalkova, L.
  • Structural Genomics Consortium (SGC)
  • DOI: 10.2210/pdb2nzt/pdb

The Pent-4-enoyl Group: A Novel Amine-Protecting Group That Is Readily Cleaved under Mild Conditions
journal, December 1995

  • Madsen, Robert; Roberts, Carmichael; Fraser-Reid, Bert
  • The Journal of Organic Chemistry, Vol. 60, Issue 24
  • DOI: 10.1021/jo00129a036

Human Hexokinase II: Sequence and Homology to Other Hexokinases
journal, November 1993

  • Deeb, S. S.; Malkki, M.; Laakso, M.
  • Biochemical and Biophysical Research Communications, Vol. 197, Issue 1
  • DOI: 10.1006/bbrc.1993.2442

Crystal structure of the human glucose transporter GLUT1
journal, May 2014

    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    New strategies for targeting glucose metabolism-mediated acidosis for colorectal cancer therapy: WANG et al.
    journal, August 2018

    • Wang, Gang; Wang, Jun-Jie; Yin, Pei-Hao
    • Journal of Cellular Physiology, Vol. 234, Issue 1
    • DOI: 10.1002/jcp.26917

    Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation
    journal, April 2018

    Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin
    journal, January 2018

    • DeWaal, Dannielle; Nogueira, Veronique; Terry, Alexander R.
    • Nature Communications, Vol. 9, Issue 1
    • DOI: 10.1038/s41467-017-02733-4

    Competitive glucose metabolism as a target to boost bladder cancer immunotherapy
    journal, January 2020

    • Afonso, Julieta; Santos, Lúcio L.; Longatto-Filho, Adhemar
    • Nature Reviews Urology, Vol. 17, Issue 2
    • DOI: 10.1038/s41585-019-0263-6

    Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes
    journal, May 2019

    • Palombo, Ramona; Caporali, Sabrina; Falconi, Mattia
    • International Journal of Molecular Sciences, Vol. 20, Issue 11
    • DOI: 10.3390/ijms20112689

    A Novel Multiple-Read Screen for Metabolically Active Compounds Based on a Genetically Encoded FRET Sensor for ATP
    journal, June 2018

    • Zhao, Ziyan; Rajagopalan, Rahul; Zweifach, Adam
    • SLAS DISCOVERY: Advancing the Science of Drug Discovery, Vol. 23, Issue 9
    • DOI: 10.1177/2472555218780636

    A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers
    journal, June 2018

    Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2
    journal, April 2017

    • Li, Wei; Zheng, Mengzhu; Wu, Shuangping
    • Journal of Experimental & Clinical Cancer Research, Vol. 36, Issue 1
    • DOI: 10.1186/s13046-017-0530-4

    Identification of alkaline pH optimum of human glucokinase because of ATP-mediated bias correction in outcomes of enzyme assays
    journal, August 2019

    Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin
    journal, January 2018

    • DeWaal, Dannielle; Nogueira, Veronique; Terry, Alexander R.
    • Nature Communications, Vol. 9, Issue 1
    • DOI: 10.1038/s41467-017-02733-4

    Identification of alkaline pH optimum of human glucokinase because of ATP-mediated bias correction in outcomes of enzyme assays
    journal, August 2019

    The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation
    journal, February 2018

    • Nawaz, Mir Hussain; Ferreira, Juliana C.; Nedyalkova, Lyudmila
    • Bioscience Reports, Vol. 38, Issue 1
    • DOI: 10.1042/bsr20171666

    A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers
    journal, June 2018

    Regulatory Role of Hexokinase 2 in Modulating Head and Neck Tumorigenesis
    journal, March 2020

    Luteolin-7-O-β-d-Glucoside Inhibits Cellular Energy Production Interacting with HEK2 in Keratinocytes
    journal, May 2019

    • Palombo, Ramona; Caporali, Sabrina; Falconi, Mattia
    • International Journal of Molecular Sciences, Vol. 20, Issue 11
    • DOI: 10.3390/ijms20112689

    Predictors of functional benefit of hepatitis C therapy in a ‘real-life’ cohort
    journal, February 2018

    • Steinebrunner, Niels; Stein, Kerstin; Sandig, Catharina
    • World Journal of Gastroenterology, Vol. 24, Issue 7
    • DOI: 10.3748/wjg.v24.i7.852

    Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation
    journal, April 2018

      Sort by:
      [ × clear filter / sort ]

      Figures / Tables found in this record:

      Figure 1 (p. 2)figure
      Table 1 (p. 2)table
      Scheme 1 (p. 3)figure
      Table 2 (p. 3)table
      Table 3 (p. 4)table
      Figure 2 (p. 5)figure
        [ × clear filter / sort ]
        Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

        Similar Records in DOE PAGES and OSTI.GOV collections: