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Hypoxia is a frequent characteristic of solid tumor growth, that appears as the tumor mass outgrows the existing vascular supply. The presence of hypoxia in solid tumors strongly contributes to their malignant phenotype by increasing angiogenesis, migration, clonal selection of mutations in anti-apoptotic genes (e.g. in TP53 or Ras), and maintaining the undifferentiated state of cancer stem cells. Furthermore, the hypoxic areas of solid tumors are resistant to traditional chemo- and radio-therapies. Altogether, the properties of hypoxic tumor cells make them an important therapeutic target. A unifying property of these cells is their expression of HIF-1, a key transcription factor that coordinates adaptive responses to hypoxia, providing cancer cells the means to survive and proliferate under hypoxic conditions. We and others have shown that disrupting HIF-1 function significantly inhibits tumor growth, highlighting the importance of developing small molecules that could antagonize the HIF-1 pathway. To identify specific small molecule inhibitors of HIF-1, we screened a combinatorial library of natural product-like compounds using a cell-based assay for HIF activity, and discovered a new class of selective HIF-1 inhibitors. These studies led to the lead inhibitor, KCN1 (IC50 ~ 4 uM), which potently reduces hypoxic levels of HIF-1α in glioma cell lines, while exerting minimal effects on the levels of HIF-1β, other short-lived proteins, or control proteins. Furthermore, KCN1 action was found to be specific to hypoxia and was independent of the phosphorylation state of major cellular signaling molecules. Pharmacokinetic experiments demonstrated the biodistribution of KCN1 and its accumulation in an orthotopic brain tumor. Pharmacodynamic measurements evidenced that HIF-1 signaling was inhibited in subcutaneous tumor xenografts. Systemic administration of KCN1 in nu/nu mice harboring sc human glioblastoma xenografts evidenced clear anti-tumor effects. Expansion of these data in other tumor models, as well as experiments addressing the molecular mechanism of KCN1 will be presented.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA