6KPS

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

Summary for 6KPS

• Entry DOI: 10.2210/pdb6kps/pdb
• Related: 6KOF
• Descriptor: 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)
• Functional Keywords: tryptophan catabolism, heme, iron, metal binding, kynurenine, immunity, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 92724.24

Authors

Peng, Y.H.,Wu, S.Y. (deposition date: 2019-08-16, release date: 2020-03-25, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.249 Å)