title: 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).
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.
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Darby G
authors.initials: DG
authors.lastname: Brooke
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: van Dam
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Colin K W
authors.initials: CK
authors.lastname: Watts
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Khoury
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Dziadek
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Hilary
authors.initials: H
authors.lastname: Brooks
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Lisa-Jane K
authors.initials: LJ
authors.lastname: Graham
authors.affiliation: 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.
authors.forename: Jack U
authors.initials: JU
authors.lastname: Flanagan
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011724:Pyridazines; D054852:Small Molecule Libraries; C062482:pyridazine; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2
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