6FMD
Targeting myeloid differentiation using potent human dihydroorotate dehydrogenase (hDHODH) inhibitors based on 2-hydroxypyrazolo[1,5-a]pyridine scaffold
Summary for 6FMD
| Entry DOI | 10.2210/pdb6fmd/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, 2-oxidanyl-~{N}-[2,3,5,6-tetrakis(fluoranyl)-4-phenyl-phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide, CHLORIDE ION, ... (9 entities in total) |
| Functional Keywords | dhodh, inhibitor complex, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 45637.54 |
| Authors | Goyal, P.,Jarva, M.,Andersson, M.,Lolli, M.L.,Friemann, R. (deposition date: 2018-01-30, release date: 2018-07-11, Last modification date: 2024-01-17) |
| Primary citation | Sainas, S.,Pippione, A.C.,Lupino, E.,Giorgis, M.,Circosta, P.,Gaidano, V.,Goyal, P.,Bonanni, D.,Rolando, B.,Cignetti, A.,Ducime, A.,Andersson, M.,Jarva, M.,Friemann, R.,Piccinini, M.,Ramondetti, C.,Buccinna, B.,Al-Karadaghi, S.,Boschi, D.,Saglio, G.,Lolli, M.L. Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors. J. Med. Chem., 61:6034-6055, 2018 Cited by PubMed Abstract: Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors. PubMed: 29939742DOI: 10.1021/acs.jmedchem.8b00373 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.58 Å) |
Structure validation
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