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.