Format

Send to

Choose Destination
Bioorg Med Chem. 2014 Feb 1;22(3):1029-39. doi: 10.1016/j.bmc.2013.12.041. Epub 2013 Dec 30.

Targeting the Warburg Effect in cancer; relationships for 2-arylpyridazinones as inhibitors of the key glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3).

Author information

1
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
2
Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
3
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
4
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.ac.nz.

Abstract

High-throughput screening of a small-molecule library identified a 5-triazolo-2-arylpyridazinone as a novel inhibitor of the important glycolytic enzyme 6-phosphofructo-2-kinase/2,6-bisphosphatase 3 (PFKFB3). Such inhibitors are of interest due to PFKFB3's control of the important glycolytic pathway used by cancer cells to generate ATP. A series of analogues was synthesized to study structure-activity relationships key to enzyme inhibition. Changes to the triazolo or pyridazinone rings were not favoured, but limited-size substitutions on the aryl ring provided modest increases in potency against the enzyme. Selected analogues and literature-described inhibitors were evaluated for their ability to suppress the glycolytic pathway, as detected by a decrease in lactate production, but none of these compounds demonstrated such suppression at non-cytotoxic concentrations.

KEYWORDS:

(2,2,6,2-tetramethylpiperidin-1-yl)oxy; 6-phosphofructo-1-kinase; 6-phosphofructo-2-kinase/2,6-bisphosphatase 3; BCA; ECAR; F1,6-BP; F2,6-BP; F6P; Glycolysis; PFK-1; PFKFB3; Pyridazinone; RIPA; TEMPO; Warburg Effect; bicinchoninic acid assay; extracellular acidification rate; fructose-1,6-bisphosphate; fructose-2,6-bisphosphate; fructose-6-phosphate; radioimmunoprecipitation assay

PMID:
24398380
DOI:
10.1016/j.bmc.2013.12.041
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center