American Chemical Society
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Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2α Inhibitors

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posted on 2023-07-05, 12:33 authored by Hans-Peter Buchstaller, Ada Sala-Hojman, Matthias Leiendecker, Joachim Albers, Uwe Anlauf, Nina Berges, Liming Dong, Thomas Fuchß, Martina Germann, Tim Knehans, Mireille Krier, Marc Lecomte, Daniel Müller, Sandra R. Müller, Birgitta Leuthner, Ralph Lindemann, Djordje Musil, Mateusz Nowak, Vivian Reither, Corinna Rettig, Christina E. M. Schindler, Urszula Pakulska, Dieter Spuck, Ansgar Wegener, Adrian Zarębski
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2α has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2α PAS B domain, can alter its conformation and disturb the activity of the HIF dimer complex. Herein, the design, synthesis, and systematic SAR exploration of cycloalkyl[c]thiophenes as novel HIF-2α inhibitors are described, providing the first chemotype featuring an alkoxy–aryl scaffold. X-ray data confirmed the ability of these inhibitors to induce perturbation of key amino acids by appropriately presenting key pharmacophoric elements in the hydrophobic cavity. Selected compounds showed inhibition of VEGF-A secretion in cancer cells and prevention of Arg1 expression and activity in IL4-stimulated macrophages. Moreover, in vivo target gene modulation was demonstrated with compound 35r. Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.