7z6c | pdb_00007z6c

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.

spinqualitylabelsall models 7z6c, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7z6c is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, FMN, IEQ, ORO, P6G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PYRD_HUMAN Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:263750; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases. Function PYRD_HUMAN Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMed 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 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 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 (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 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. 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.,Sainas S, Giorgis M, Circosta P, Poli G, Alberti M, Passoni A, Gaidano V, Pippione AC, Vitale N, Bonanni D, Rolando B, Cignetti A, Ramondetti C, Lanno A, Ferraris DM, Canepa B, Buccinna B, Piccinini M, Rizzi M, Saglio G, Al-Karadaghi S, Boschi D, Miggiano R, Tuccinardi T, Lolli ML J Med Chem. 2022 Oct 13;65(19):12701-12724. doi: 10.1021/acs.jmedchem.2c00496., Epub 2022 Sep 26. PMID:36162075 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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