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Crystal structure of indoleamine 2,3-dioxygenagse 1 (IDO1) in complex with compound 12Crystal structure of indoleamine 2,3-dioxygenagse 1 (IDO1) in complex with compound 12
Structural highlights
FunctionI23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen.[1] Publication Abstract from PubMedIndoleamine 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 N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 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-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 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 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future. Unique Sulfur-Aromatic Interactions Contribute to the Binding of Potent Imidazothiazole Indoleamine 2,3-Dioxygenase Inhibitors.,Peng YH, Liao FY, Tseng CT, Kuppusamy R, Li AS, Chen CH, Fan YS, Wang SY, Wu MH, Hsueh CC, Chang JY, Lee LC, Shih C, Shia KS, Yeh TK, Hung MS, Kuo CC, Song JS, Wu SY, Ueng SH J Med Chem. 2020 Feb 27;63(4):1642-1659. doi: 10.1021/acs.jmedchem.9b01549. Epub , 2020 Feb 10. PMID:31961685[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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