Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer
| العنوان: | Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer |
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| المؤلفون: | John O. Trent, Sucheta Telang, Rebecca Redman, Julie O'Neal, Jason Chesney, Brian F. Clem, Amy L. Clem, Alden C. Klarer, Daniel Alan Kerr, Yoannis Imbert-Fernandez, Donald M. Miller, Gilles Tapolsky |
| المصدر: | Molecular Cancer Therapeutics. 12:1461-1470 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Models, Molecular, Cancer Research, Cell Survival, Phosphofructokinase-2, Molecular Conformation, Phases of clinical research, Antineoplastic Agents, Apoptosis, Pharmacology, Biology, Jurkat cells, Article, Small Molecule Libraries, Jurkat Cells, Mice, In vivo, Cell Line, Tumor, Neoplasms, Animals, Humans, PTEN, Phosphofructokinase 2, Molecular Targeted Therapy, Enzyme Inhibitors, Protein kinase B, Xenograft Model Antitumor Assays, Tumor Burden, Disease Models, Animal, Glucose, Oncology, Cancer cell, biology.protein, Female, Drug Screening Assays, Antitumor, Protein Binding |
| الوصف: | 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. Mol Cancer Ther; 12(8); 1461–70. ©2013 AACR. |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3760e55f5c9a3d7e4289ce1bc3b391adTest https://doi.org/10.1158/1535-7163.mct-13-0097Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3760e55f5c9a3d7e4289ce1bc3b391ad |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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