8K4F

DHODH in complex with compound A0

Summary for 8K4F

• Entry DOI: 10.2210/pdb8k4f/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, SULFATE ION, TETRAETHYLENE GLYCOL, ... (9 entities in total)
• Functional Keywords: inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41711.94

Authors

Jian, L.,Sun, Q. (deposition date: 2023-07-18, release date: 2024-05-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.48 Å)