8ck8 | pdb_00008ck8
STRUCTURE OF HIF2A-ARNT HETERODIMER IN COMPLEX WITH (S)-1-Cyclohexyloxy-5,5-difluoro-3-methanesulfonyl-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ol
Structural highlights
DiseaseEPAS1_HUMAN Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:611783. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.[1] [2] [3] [4] FunctionEPAS1_HUMAN Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD. Publication Abstract from PubMedHypoxia-inducible factors (HIFs) are heterodimeric transcription factors induced in diverse pathophysiological settings. Inhibition of HIF-2alpha has become a strategy for cancer treatment since the discovery that small molecules, upon binding into a small cavity of the HIF-2alpha 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-2alpha 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-2alpha inhibitors represent valuable tools for investigating selective HIF-2alpha inhibition and its effect on tumor biology. Discovery of Cycloalkyl[c]thiophenes as Novel Scaffolds for Hypoxia-Inducible Factor-2alpha Inhibitors.,Buchstaller HP, 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 SR, Leuthner B, Lindemann R, Musil D, Nowak M, Reither V, Rettig C, Schindler CEM, Pakulska U, Spuck D, Wegener A, Zarebski A J Med Chem. 2023 Jul 13;66(13):8666-8686. doi: 10.1021/acs.jmedchem.3c00332. Epub , 2023 Jul 5. PMID:37403966[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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