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.

7Z6C の概要

• エントリーDOI: 10.2210/pdb7z6c/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (7 entities in total)
• 機能のキーワード: dihydroorotate dehydrogenase, inhibitor, complex, acute myeloid leukaemia., oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41080.62

構造登録者

Alberti, M.,Lolli, M.L.,Boschi, D.,Sainas, S.,Rizzi, M.,Ferraris, D.M.,Miggiano, R. (登録日: 2022-03-11, 公開日: 2022-10-12, 最終更新日: 2024-01-31)

主引用文献

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

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: 36162075
DOI: 10.1021/acs.jmedchem.2c00496

実験手法

X-RAY DIFFRACTION (1.85 Å)