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http://ir.nhri.org.tw/handle/3990099045/12524
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| Title: | Unique sulfur-aromatic interactions contribute to the binding of potent imidazothiazole indoleamine 2,3-Dioxygenase inhibitors |
| Authors: | 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 |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| 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 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. |
| Date: | 2020-02-10 |
| Relation: | Journal of Medicinal Chemistry. 2020 Feb 10;63(4):1642-1659. |
| Link to: | http://dx.doi.org/10.1021/acs.jmedchem.9b01549 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000517673100013 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85081157558 |
| Appears in Collections: | [伍素瑩] 期刊論文
[翁紹華] 期刊論文
[石全(2014-2017)] 期刊論文
[夏克山] 期刊論文
[葉燈光] 期刊論文
[郭靜娟] 期刊論文
[洪明秀] 期刊論文
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| PUB31961685.pdf | | 4667Kb | Adobe PDF | 479 | View/Open |
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