9IIF

Factor inhibiting HIF-1 alpha in complex with Zn(II) and Desidustat

This is a non-PDB format compatible entry.

Summary for 9IIF

• Entry DOI: 10.2210/pdb9iif/pdb
• Descriptor: Hypoxia-inducible factor 1-alpha inhibitor, SULFATE ION, 2-[[1-(cyclopropylmethoxy)-2-oxidanyl-4-oxidanylidene-quinolin-3-yl]carbonylamino]ethanoic acid, ... (5 entities in total)
• Functional Keywords: factor-inhibiting hypoxia-inducible factor, fih, 2og dependent dioxygenase, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41494.50

Authors

Nakashima, Y.,Corner, T.P.,Brewitz, L.,Schofield, C.J. (deposition date: 2024-06-20, release date: 2025-01-29)

Primary citation

Corner, T.P.,Salah, E.,Tumber, A.,Kaur, S.,Nakashima, Y.,Allen, M.D.,Schnaubelt, L.I.,Fiorini, G.,Brewitz, L.,Schofield, C.J.
Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat.
Chemmedchem, 19:e202400504-e202400504, 2024

PubMed Abstract: Prolyl hydroxylase domain-containing proteins 1-3 (PHD1-3) are 2-oxoglutarate (2OG)-dependent oxygenases catalysing C-4 hydroxylation of prolyl residues in α-subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), modifications that promote HIF-α degradation via the ubiquitin-proteasome pathway. Pharmacological inhibition of the PHDs induces HIF-α stabilisation, so promoting HIF target gene transcription. PHD inhibitors are used to treat anaemia caused by chronic kidney disease (CKD) due to their ability to stimulate erythropoietin (EPO) production. We report studies on the effects of the approved PHD inhibitors Desidustat and Enarodustat, and the clinical candidate TP0463518, on activities of a representative set of isolated recombinant human 2OG oxygenases. The three molecules manifest selectivity for PHD inhibition over that of the other 2OG oxygenases evaluated. We obtained crystal structures of Desidustat and Enarodustat in complex with the human 2OG oxygenase factor inhibiting hypoxia-inducible factor-α (FIH), which, together with modelling studies, inform on the binding modes of Desidustat and Enarodustat to active site Fe(II) in 2OG oxygenases, including PHD1-3. The results will help in the design of selective inhibitors of both the PHDs and other 2OG oxygenases, which are of medicinal interest due to their involvement inter alia in metabolic regulation, epigenetic signalling, DNA-damage repair, and agrochemical resistance.

PubMed: 39291299
DOI: 10.1002/cmdc.202400504

Experimental method

X-RAY DIFFRACTION (2.16 Å)