Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat
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.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Crystallographic and Selectivity Studies on the Approved HIF Prolyl Hydroxylase Inhibitors Desidustat and Enarodustat ; day:08 ; month:11 ; year:2024 ; extent:13
ChemMedChem ; (08.11.2024) (gesamt 13)
- Urheber
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Corner, Thomas P.
Salah, Eidarus
Tumber, Anthony
Kaur, Samanpreet
Nakashima, Yu
Allen, Mark D.
Schnaubelt, Lara I.
Fiorini, Giorgia
Brewitz, Lennart
Schofield, Christopher
- DOI
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10.1002/cmdc.202400504
- URN
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urn:nbn:de:101:1-2411091414473.754392782532
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:37 MESZ
Datenpartner
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Beteiligte
- Corner, Thomas P.
- Salah, Eidarus
- Tumber, Anthony
- Kaur, Samanpreet
- Nakashima, Yu
- Allen, Mark D.
- Schnaubelt, Lara I.
- Fiorini, Giorgia
- Brewitz, Lennart
- Schofield, Christopher
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Correction to: HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction induced injury
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The impact of neuronal HIF prolyl 4-hydroxylase 2 inactivation on ischemic stroke recovery in mice
Structure‐Activity Relationship and Crystallographic Studies on 4‐Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors
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Bedeutung des HIF-Prolyl-Hydroxylase 1 (PHS1) Enzyms bei der Leberregeneration
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