6KPS

Crystal structure of indoleamine 2,3-dioxygenagse 1 (IDO1) in complex with compound 36

6KPS の概要

• エントリーDOI: 10.2210/pdb6kps/pdb
• 関連するPDBエントリー: 6KOF
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, 1-(4-cyanophenyl)-3-[[3-(2-cyclopropylethynyl)imidazo[2,1-b][1,3]thiazol-5-yl]methyl]urea, ... (4 entities in total)
• 機能のキーワード: tryptophan catabolism, heme, iron, metal binding, kynurenine, immunity, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92724.24

構造登録者

Peng, Y.H.,Wu, S.Y. (登録日: 2019-08-16, 公開日: 2020-03-25, 最終更新日: 2023-11-22)

主引用文献

Peng, Y.H.,Liao, F.Y.,Tseng, C.T.,Kuppusamy, R.,Li, A.S.,Chen, C.H.,Fan, Y.S.,Wang, S.Y.,Wu, M.H.,Hsueh, C.C.,Chang, J.Y.,Lee, L.C.,Shih, C.,Shia, K.S.,Yeh, T.K.,Hung, M.S.,Kuo, C.C.,Song, J.S.,Wu, S.Y.,Ueng, S.H.
Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors.
J.Med.Chem., 63:1642-1659, 2020

PubMed Abstract: Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor -(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-][1,2,4]triazol-3-yl)thio)acetamide through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-]thiazol-5-yl)thiourea (hIDO IC = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.

PubMed: 31961685
DOI: 10.1021/acs.jmedchem.9b01549

実験手法

X-RAY DIFFRACTION (2.249 Å)