title: Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer.
abstract: In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1α, and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator of 6-phosphofructo-1-kinase, a key step of glycolysis. Previously, a weak competitive inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found to reduce the glucose metabolism and proliferation of cancer cells. We have synthesized 73 derivatives of 3PO and screened each compound for activity against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), was selected for further preclinical evaluation of its pharmacokinetic, antimetabolic, and antineoplastic properties in vitro and in vivo. We found that PFK15 causes a rapid induction of apoptosis in transformed cells, has adequate pharmacokinetic properties, suppresses the glucose uptake and growth of Lewis lung carcinomas in syngeneic mice, and yields antitumor effects in three human xenograft models of cancer in athymic mice that are comparable to U.S. Food and Drug Administration-approved chemotherapeutic agents. As a result of this study, a synthetic derivative and formulation of PFK15 has undergone investigational new drug (IND)-enabling toxicology and safety studies. A phase I clinical trial of its efficacy in advanced cancer patients will initiate in 2013 and we anticipate that this new class of antimetabolic agents will yield acceptable therapeutic indices and prove to be synergistic with agents that disrupt neoplastic signaling.
authors.affiliation: Division of Medical Oncology and Hematology, Department of Medicine, Louisville, KY, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Clem
authors.forename: Julie
authors.initials: J
authors.lastname: O'Neal
authors.forename: Gilles
authors.initials: G
authors.lastname: Tapolsky
authors.forename: Amy L
authors.initials: AL
authors.lastname: Clem
authors.forename: Yoannis
authors.initials: Y
authors.lastname: Imbert-Fernandez
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kerr
authors.forename: Alden C
authors.initials: AC
authors.lastname: Klarer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redman
authors.forename: Donald M
authors.initials: DM
authors.lastname: Miller
authors.forename: John O
authors.initials: JO
authors.lastname: Trent
authors.forename: Sucheta
authors.initials: S
authors.lastname: Telang
authors.forename: Jason
authors.initials: J
authors.lastname: Chesney
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054852:Small Molecule Libraries; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D005947:Glucose