7Z6C
Crystal structure of human Dihydroorotate Dehydrogenase in complex with the inhibitor 2-Hydroxy-N-(2-ispropyl-5-methyl-4-phenoxyphenyl)pyrazolo[1,5-a]pyridine-3-carboxamide.
Summary for 7Z6C
| Entry DOI | 10.2210/pdb7z6c/pdb |
| Descriptor | Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (7 entities in total) |
| Functional Keywords | dihydroorotate dehydrogenase, inhibitor, complex, acute myeloid leukaemia., oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41080.62 |
| Authors | Alberti, M.,Lolli, M.L.,Boschi, D.,Sainas, S.,Rizzi, M.,Ferraris, D.M.,Miggiano, R. (deposition date: 2022-03-11, release date: 2022-10-12, Last modification date: 2024-01-31) |
| Primary citation | Sainas, S.,Giorgis, M.,Circosta, P.,Poli, G.,Alberti, M.,Passoni, A.,Gaidano, V.,Pippione, A.C.,Vitale, N.,Bonanni, D.,Rolando, B.,Cignetti, A.,Ramondetti, C.,Lanno, A.,Ferraris, D.M.,Canepa, B.,Buccinna, B.,Piccinini, M.,Rizzi, M.,Saglio, G.,Al-Karadaghi, S.,Boschi, D.,Miggiano, R.,Tuccinardi, T.,Lolli, M.L. Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a ]pyridine Scaffold: SAR of the Aryloxyaryl Moiety. J.Med.Chem., 65:12701-12724, 2022 Cited by PubMed Abstract: In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound (IC 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC 74 nM), superior to those of brequinar (EC 249 nM) and boosted when in combination with dipyridamole. Finally, compound has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML. PubMed: 36162075DOI: 10.1021/acs.jmedchem.2c00496 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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