Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors
Copyright © 2023 Elsevier Ltd. All rights reserved..
A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STINGR232 knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:95 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 95(2023) vom: 15. Nov., Seite 117502 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chang, Po-Wei [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.11.2023 Date Revised 22.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2023.117502 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM363584145 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STINGR232 knock-in THP-1 reporter cell line. The half-maximal inhibitory concentration of the most potent compound, 21, was 11.5 nM. The molecular docking analysis of compound 21 and STING combined with the SAR study suggested that the meta- and para-positions of the benzene ring of the phenylcarbamic amide moiety could be structurally modified by introducing halides or alkyl substituents | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Cyclic AMP-GMP synthase | |
| 650 | 4 | |a Interferon regulatory factor 3 | |
| 650 | 4 | |a STING inhibitor | |
| 650 | 4 | |a Stimulator of interferon genes | |
| 650 | 4 | |a cGAS-STING pathway | |
| 650 | 7 | |a Amides |2 NLM | |
| 650 | 7 | |a Nucleotidyltransferases |2 NLM | |
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| 700 | 1 | |a Wang, Jing-Ya |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wan-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wei-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Mine-Hsine |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Jen-Shin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Liuh-Yow |e verfasserin |4 aut | |
| 700 | 1 | |a Tung, Chun-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Chi, Ya-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Ueng, Shau-Hua |e verfasserin |4 aut | |
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