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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)


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.

Type Journal
ISBN 1464-3391 (Electronic) 0968-0896 (Linking)
Authors Brooke, D. G.; van Dam, E. M.; Watts, C. K.; Khoury, A.; Dziadek, M. A.; Brooks, H.; Graham, L. J.; Flanagan, J. U.; Denny, W. A.;
Published Date 2014-01-01
Published Volume 22
Published Issue 3
Published Pages 1029-39
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version