8CK3

STRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (S)-1-(3,5-Difluoro-phenyl)-5,5-difluoro-3-methanesulfonyl-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ol

Summary for 8CK3

• Entry DOI: 10.2210/pdb8ck3/pdb
• Descriptor: Endothelial PAS domain-containing protein 1, Aryl hydrocarbon receptor nuclear translocator, (4~{S})-1-[3,5-bis(fluoranyl)phenyl]-5,5-bis(fluoranyl)-3-methylsulfonyl-4,6-dihydrocyclopenta[c]thiophen-4-ol, ... (5 entities in total)
• Functional Keywords: hypoxia-inducible factor, bhlh-pas, hif-2-alpha, arnt, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 28339.99

Authors

Musil, D.,Lehmannn, M.,Diehl, L. (deposition date: 2023-02-14, release date: 2023-07-19, Last modification date: 2024-06-19)

Primary citation

Buchstaller, H.P.,Sala-Hojman, A.,Leiendecker, M.,Albers, J.,Anlauf, U.,Berges, N.,Dong, L.,Fuchss, T.,Germann, M.,Knehans, T.,Krier, M.,Lecomte, M.,Muller, D.,Muller, S.R.,Leuthner, B.,Lindemann, R.,Musil, D.,Nowak, M.,Reither, V.,Rettig, C.,Schindler, C.E.M.,Pakulska, U.,Spuck, D.,Wegener, A.,Zarebski, A.
Discovery of Cycloalkyl[ c ]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2 alpha Inhibitors.
J.Med.Chem., 66:8666-8686, 2023

PubMed Abstract: 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[]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 . Thus, the disclosed HIF-2α inhibitors represent valuable tools for investigating selective HIF-2α inhibition and its effect on tumor biology.

PubMed: 37403966
DOI: 10.1021/acs.jmedchem.3c00332

Experimental method

X-RAY DIFFRACTION (1.707 Å)