ArticleChemMedChem2021
Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.
Article in ChemMedChem, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 34 citations in OpenAlex.
- Clinically approved HIF-PHIs modulate redox metabolism, cell growth, and angiogenesis independent of HIF-1α/HIF-2α.Redox biology · 2026Article
- Profiling Inhibitor Scaffolds for the Cancer Target Jumonji-C Domain-Containing Protein 6.ChemMedChem · 2025Article
- Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human γ-Butyrobetaine Hydroxylase.Journal of medicinal chemistry · 2025Article
- Human prolyl hydroxylase domain 2 reacts with OScientific reports · 2024Article
- The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.Nature cancer · 2024Article
- Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2024Review
- Structure-guided optimisation ofChemical science · 2023Article
- Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.Proteins · 2023Article
- 5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.Journal of medicinal chemistry · 2023Article
- Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5.Scientific reports · 2022Article
- Conservation of the unusual dimeric JmjC fold of JMJD7 from Drosophila melanogaster to humans.Scientific reports · 2022Article
- Roxadustat: Not just for anemia.Frontiers in pharmacology · 2022Review
- Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases.Frontiers in pharmacology · 2022Review
- Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.Journal of medicinal chemistry · 2021Article
- Structural Basis of Prolyl Hydroxylase Domain Inhibition by Molidustat.ChemMedChem · 2021Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 3 countries.
Funding
Abstract
Human prolyl-hydroxylases (PHDs) are hypoxia-sensing 2-oxoglutarate (2OG) oxygenases, catalysis by which suppresses the transcription of hypoxia-inducible factor target genes. PHD inhibition enables the treatment of anaemia/ischaemia-related disease. The PHD inhibitor Molidustat is approved for the treatment of renal anaemia; it differs from other approved/late-stage PHD inhibitors in lacking a glycinamide side chain. The first reported crystal structures of Molidustat and IOX4 (a brain-penetrating derivative) complexed with PHD2 reveal how their contiguous triazole, pyrazolone and pyrimidine/pyridine rings bind at the active site. The inhibitors bind to the active-site metal in a bidentate manner through their pyrazolone and pyrimidine nitrogens, with the triazole π-π-stacking with Tyr303 in the 2OG binding pocket. Comparison of the new structures with other PHD inhibitor complexes reveals differences in the conformations of Tyr303, Tyr310, and a mobile loop linking β2-β3, which are involved in dynamic substrate binding/product release.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.