9JTX
Factor inhibiting HIF-1 alpha in complex with Zn(II) and 2-(4-hydroxy-2-oxo-1-(thiazol-4-ylmethoxy)-1,2-dihydroquinoline-3-carboxamido)-2-methylpropanoic acid
This is a non-PDB format compatible entry.
Summary for 9JTX
| Entry DOI | 10.2210/pdb9jtx/pdb |
| Descriptor | Hypoxia-inducible factor 1-alpha inhibitor, SULFATE ION, 2-methyl-2-[[4-oxidanyl-2-oxidanylidene-1-(1,3-thiazol-4-ylmethoxy)quinolin-3-yl]carbonylamino]propanoic 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 | 41469.54 |
| Authors | Nakashima, Y.,Corner, T.P.,Brewitz, L.,Schofield, C.J. (deposition date: 2024-10-07, release date: 2025-04-30, Last modification date: 2025-05-21) |
| Primary citation | Corner, T.P.,Tumber, A.,Salah, E.,Jabbary, M.,Nakashima, Y.,Schnaubelt, L.I.,Basak, S.,Alshref, F.M.,Brewitz, L.,Schofield, C.J. Derivatives of the Clinically Used HIF Prolyl Hydroxylase Inhibitor Desidustat Are Efficient Inhibitors of Human gamma-Butyrobetaine Hydroxylase. J.Med.Chem., 68:9777-9798, 2025 Cited by PubMed Abstract: The 2-oxoglutarate (2OG)/Fe(II)-dependent γ-butyrobetaine hydroxylase (BBOX) catalyzes the final step in l-carnitine biosynthesis, , stereoselective C-3 oxidation of γ-butyrobetaine (GBB). BBOX inhibition is a validated clinical strategy to modulate l-carnitine levels and to enhance cardiovascular efficiency. Reported BBOX inhibitors, including the clinically used cardioprotective agent Mildronate, manifest moderate inhibitory activity , limited selectivity, and/or unfavorable physicochemical properties, indicating a need for improved BBOX inhibitors. We report that the clinically used hypoxia-inducible factor-α prolyl residue hydroxylase (PHD) inhibitors Desidustat, Enarodustat, and Vadadustat efficiently inhibit isolated recombinant BBOX, suggesting that BBOX inhibition by clinically used PHD inhibitors should be considered as a possible off-target effect. Structure-activity relationship studies on the Desidustat scaffold enabled development of potent BBOX inhibitors that manifest high levels of selectivity for BBOX inhibition over representative human 2OG oxygenases, including PHD2. The Desidustat derivatives will help to enable investigations into the biological roles of l-carnitine and the therapeutic potential of BBOX inhibition. PubMed: 40263713DOI: 10.1021/acs.jmedchem.5c00586 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.08 Å) |
Structure validation
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