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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 DOI10.2210/pdb8ck3/pdb
DescriptorEndothelial 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 Keywordshypoxia-inducible factor, bhlh-pas, hif-2-alpha, arnt, transcription
Biological sourceHomo sapiens (human)
More
Total number of polymer chains2
Total formula weight28339.99
Authors
Musil, D.,Lehmannn, M.,Diehl, L. (deposition date: 2023-02-14, release date: 2023-07-19, Last modification date: 2024-06-19)
Primary citationBuchstaller, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.707 Å)
Structure validation

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