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Background In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1a, and activation of Ras and AKT converge to increase the activity of a regulator of glycolysis, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). This enzyme synthesizes fructose-2,6-bisphosphate (F2,6BP), which is an activator of 6-phosphofructo1-kinase, a key step of glycolysis that is tightly controlled by multiple metabolic feedback mechanisms. We recently identified the first competitive small molecule inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), and have now sought to develop a more potent PFKFB3 inhibitor with improved PK properties for testing in clinical trials. Materials and methods Methods included recombinant PFKFB3 assays, PK studies using mass spectrometry, pre-clinical toxicity and efficacy studies, Western blot analyses for HIF-1a and PFKFB3 in A375 melanoma cells, F2,6BP assessments and flow cytometry for apoptosis. Results

Discovery of a PFKFB3 inhibitor for phase I trial testing that synergizes with the B-Raf inhibitor vemurafenib