Targeting 6-Phosphofructo-2-Kinase (PFKFB3) as a Therapeutic Strategy against Cancer

摘要: In human cancers, loss of PTEN, stabilization hypoxia inducible factor-1α, and activation Ras AKT converge to increase the activity a key regulator glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator 6-phosphofructo-1-kinase, step glycolysis. Previously, weak competitive inhibitor PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found reduce glucose metabolism proliferation cancer cells. We have synthesized 73 derivatives 3PO screened each compound for against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15), selected further preclinical evaluation its pharmacokinetic, antimetabolic, antineoplastic properties in vitro vivo. that PFK15 causes rapid induction apoptosis transformed cells, has adequate pharmacokinetic properties, suppresses uptake growth Lewis lung carcinomas syngeneic mice, yields antitumor effects three xenograft models athymic mice are comparable U.S. Food Drug Administration-approved chemotherapeutic agents. As result this study, synthetic derivative formulation undergone investigational new drug (IND)-enabling toxicology safety studies. A phase I clinical trial efficacy advanced patients will initiate 2013 we anticipate class antimetabolic agents yield acceptable therapeutic indices prove be synergistic with disrupt neoplastic signaling.