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

Journal Article · · ACS Medicinal Chemistry Letters
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  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
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (US). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1438892
Journal Information:
ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 3 Vol. 7; ISSN 1948-5875
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (13)

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A convenient preparation of some 2,3,4,6-tetra-O-acetyl-1,5-anhydro-d-hexitols journal December 1982
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
Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer journal August 2013
Hexokinase-2 bound to mitochondria: Cancer's stygian link to the “Warburg effect” and a pivotal target for effective therapy journal February 2009
The Pent-4-enoyl Group: A Novel Amine-Protecting Group That Is Readily Cleaved under Mild Conditions journal December 1995
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
The structure of mammalian hexokinase-1 journal July 1998
Crystal structure of the human glucose transporter GLUT1 journal May 2014
Glycolysis inhibition for anticancer treatment journal August 2006
Crystal structure of human hexokinase II journal December 2006
Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines journal August 2009
Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo journal July 2008

Cited By (13)

Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism journal February 2019
Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin journal January 2018
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
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
Predictors of functional benefit of hepatitis C therapy in a ‘real-life’ cohort journal February 2018
Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation journal April 2018
New strategies for targeting glucose metabolism-mediated acidosis for colorectal cancer therapy: WANG et al. journal August 2018
Competitive glucose metabolism as a target to boost bladder cancer immunotherapy journal January 2020
A Novel Multiple-Read Screen for Metabolically Active Compounds Based on a Genetically Encoded FRET Sensor for ATP journal June 2018
Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 journal April 2017

Figures / Tables (6)

Figure 1(p. 2)figure Figure 1
Table 1(p. 2)table Table 1
Scheme 1(p. 3)figure Scheme 1
Table 2(p. 3)table Table 2
Table 3(p. 4)table Table 3
Figure 2(p. 5)figure Figure 2

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Amides
Carbohydrates
Hexokinase 2 inhibitor
Inhibition
Inhibitors
Peptides and proteins
crystal structure
structure−activity relationship selectivity