Hypoxia-inducible factors (HIFs) are heterodimeric transcriptionfactors induced in diverse pathophysiological settings. Inhibitionof HIF-2 alpha; has become a strategy for cancer treatment since thediscovery that small molecules, upon binding into a small cavity ofthe HIF-2 alpha; PAS B domain, can alter its conformation and disturbthe activity of the HIF dimer complex. Herein, the design, synthesis,and systematic SAR exploration of cycloalkylcthiophenesas novel HIF-2 alpha; inhibitors are described, providing the firstchemotype featuring an alkoxy-aryl scaffold. X-ray data confirmedthe ability of these inhibitors to induce perturbation of key aminoacids by appropriately presenting key pharmacophoric elements in thehydrophobic cavity. Selected compounds showed inhibition of VEGF-Asecretion in cancer cells and prevention of Arg1 expression and activityin IL4-stimulated macrophages. Moreover, in vivo target gene modulationwas demonstrated with compound 35r. Thus, the disclosedHIF-2 alpha; inhibitors represent valuable tools for investigatingselective HIF-2 alpha; inhibition and its effect on tumor biology.
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