8K4F

DHODH in complex with compound A0

8K4F の概要

• エントリーDOI: 10.2210/pdb8k4f/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), mitochondrial, SULFATE ION, TETRAETHYLENE GLYCOL, ... (9 entities in total)
• 機能のキーワード: inhibitor, complex, 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: 41711.94

構造登録者

Jian, L.,Sun, Q. (登録日: 2023-07-18, 公開日: 2024-05-29)

主引用文献

Zhou, X.,Gou, K.,Xu, J.,Jian, L.,Luo, Y.,Li, C.,Guan, X.,Qiu, J.,Zou, J.,Zhang, Y.,Zhong, X.,Zeng, T.,Zhou, Y.,Xiao, Y.,Yang, X.,Chen, W.,Gao, P.,Liu, C.,Zhou, Y.,Tao, L.,Liu, X.,Cen, X.,Chen, Q.,Sun, Q.,Luo, Y.,Zhao, Y.
Discovery and Optimization of Novel h DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.
J.Med.Chem., 66:14755-14786, 2023

PubMed Abstract: As a key rate-limiting enzyme in the synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1-pyrazolo[3,4-]pyridine scaffold was identified as an DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1-pyrrolo[2,3-]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (, which was found to be the most promising and drug-like compound with potent inhibitory activity against DHODH (IC = 173.4 nM). Compound demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, exerted better therapeutic effects on ulcerative colitis than DHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, is a promising DHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

PubMed: 37870434
DOI: 10.1021/acs.jmedchem.3c01365

実験手法

X-RAY DIFFRACTION (2.48 Å)