Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect
Abstract Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for develop...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | MedComm |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mco2.70001 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594253708001280 |
|---|---|
| author | Xiyuan Wang Zhengsheng Zhan Zhen Wang Yan Zhang Kaiyan Zhao Han Li Xiaoqian Zhou Yuting Guo Fengying Fan Jian Ding Meiyu Geng Xuekui Yu Wenhu Duan Zuoquan Xie |
| author_facet | Xiyuan Wang Zhengsheng Zhan Zhen Wang Yan Zhang Kaiyan Zhao Han Li Xiaoqian Zhou Yuting Guo Fengying Fan Jian Ding Meiyu Geng Xuekui Yu Wenhu Duan Zuoquan Xie |
| author_sort | Xiyuan Wang |
| collection | DOAJ |
| description | Abstract Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non‐nucleotide STING agonist called DW18343. DW18343 showed robust activation across different STING isoforms. Crystallography analysis revealed that DW18343 binds more deeply into the ligand binding domain (LBD) pocket of STING‐H232 compared to other agonists such as MSA‐2, SR‐717, or cGAMP, which likely contributes to its high potency. DW18343 triggered downstream p‐TBK1/p‐IRF3 signaling, leading to the production of multiple cytokines. Additionally, DW18343 displayed broad and long‐lasting antitumor effects in various syngeneic mouse tumor models, whether administered locally or systemically. Moreover, DW18343 induced immune memory to combat the growth of rechallenged tumors. Finally, DW18343 was shown to be an activator of both the innate and adaptive antitumor immunity in tumor tissue, potentially explaining its strong antitumor effects in vivo. In conclusion, DW18343 serves as a novel non‐nucleotide STING agonist with systemic antitumor effect through the activation of antitumor immunity. |
| format | Article |
| id | doaj-art-f4f20cd8928a48c88b1e9a24b4593830 |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-f4f20cd8928a48c88b1e9a24b45938302025-01-20T01:45:44ZengWileyMedComm2688-26632025-01-0161n/an/a10.1002/mco2.70001Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effectXiyuan Wang0Zhengsheng Zhan1Zhen Wang2Yan Zhang3Kaiyan Zhao4Han Li5Xiaoqian Zhou6Yuting Guo7Fengying Fan8Jian Ding9Meiyu Geng10Xuekui Yu11Wenhu Duan12Zuoquan Xie13State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaSmall‐Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaCryo‐Electron Microscopy Research Center & The CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaState Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaSmall‐Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaState Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaSmall‐Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaSmall‐Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaUniversity of Chinese Academy of Sciences Beijing ChinaState Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaState Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaUniversity of Chinese Academy of Sciences Beijing ChinaSmall‐Molecule Drug Research Center Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaState Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai ChinaAbstract Agonists of the stimulator of interferon genes (STING) pathway are increasingly being recognized as a promising new approach in the treatment of cancer. Although progress in clinical trials for STING agonists in antitumor applications has been slow, there is still an urgent need for developing new potent STING agonists with versatile potential applications. Herein, we developed and identified a non‐nucleotide STING agonist called DW18343. DW18343 showed robust activation across different STING isoforms. Crystallography analysis revealed that DW18343 binds more deeply into the ligand binding domain (LBD) pocket of STING‐H232 compared to other agonists such as MSA‐2, SR‐717, or cGAMP, which likely contributes to its high potency. DW18343 triggered downstream p‐TBK1/p‐IRF3 signaling, leading to the production of multiple cytokines. Additionally, DW18343 displayed broad and long‐lasting antitumor effects in various syngeneic mouse tumor models, whether administered locally or systemically. Moreover, DW18343 induced immune memory to combat the growth of rechallenged tumors. Finally, DW18343 was shown to be an activator of both the innate and adaptive antitumor immunity in tumor tissue, potentially explaining its strong antitumor effects in vivo. In conclusion, DW18343 serves as a novel non‐nucleotide STING agonist with systemic antitumor effect through the activation of antitumor immunity.https://doi.org/10.1002/mco2.70001antitumorimmune memoryinnate immunitySTING agonist |
| spellingShingle | Xiyuan Wang Zhengsheng Zhan Zhen Wang Yan Zhang Kaiyan Zhao Han Li Xiaoqian Zhou Yuting Guo Fengying Fan Jian Ding Meiyu Geng Xuekui Yu Wenhu Duan Zuoquan Xie Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect MedComm antitumor immune memory innate immunity STING agonist |
| title | Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect |
| title_full | Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect |
| title_fullStr | Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect |
| title_full_unstemmed | Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect |
| title_short | Discovery of a non‐nucleotide stimulator of interferon genes (STING) agonist with systemic antitumor effect |
| title_sort | discovery of a non nucleotide stimulator of interferon genes sting agonist with systemic antitumor effect |
| topic | antitumor immune memory innate immunity STING agonist |
| url | https://doi.org/10.1002/mco2.70001 |
| work_keys_str_mv | AT xiyuanwang discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT zhengshengzhan discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT zhenwang discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT yanzhang discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT kaiyanzhao discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT hanli discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT xiaoqianzhou discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT yutingguo discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT fengyingfan discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT jianding discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT meiyugeng discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT xuekuiyu discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT wenhuduan discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect AT zuoquanxie discoveryofanonnucleotidestimulatorofinterferongenesstingagonistwithsystemicantitumoreffect |