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

8CK3 の概要

• エントリーDOI: 10.2210/pdb8ck3/pdb
• 分子名称: 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)
• 機能のキーワード: hypoxia-inducible factor, bhlh-pas, hif-2-alpha, arnt, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28339.99

構造登録者

Musil, D.,Lehmannn, M.,Diehl, L. (登録日: 2023-02-14, 公開日: 2023-07-19, 最終更新日: 2024-06-19)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.707 Å)