Orally Bioavailable and Site-Selective Covalent STING Inhibitor Derived from a Macrocyclic Marine Diterpenoid

被引：0

作者：

Niu, Guang-Hao ^{[1
]}

Hsiao, Wan-Chi ^{[2
,4
]}

Lee, Po-Hsun ^{[2
,4
]}

Zheng, Li-Guo ^{[3
]}

Yang, Yu-Shao ^{[5
]}

Huang, Wei-Cheng ^{[1
]}

Hsieh, Chih-Chien ^{[1
]}

Chiu, Tai-Yu ^{[1
]}

Wang, Jing-Ya ^{[1
]}

Chen, Ching-Ping ^{[1
]}

Huang, Chen-Lung ^{[1
]}

You, May-Su ^{[2
]}

Kuo, Yi-Ping ^{[5
]}

Wang, Chien-Ming ^{[2
]}

Wen, Zhi-Hong ^{[6
]}

Yu, Guann-Yi ^{[5
]}

Chen, Chiung-Tong ^{[1
]}

Chi, Ya-Hui ^{[1
]}

Tung, Chun-Wei ^{[1
]}

Hsu, Shu-Ching ^{[5
]}

Yeh, Teng-Kuang ^{[1
]}

Sung, Ping-Jyun ^{[3
]}

Zhang, Mingzi M. ^{[2
]}

Tsou, Lun Kelvin ^{[1
]}

机构：

[1] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan 35053, Miaoli, Taiwan

[2] Natl Hlth Res Inst, Inst Mol & Genom Med, Zhunan 35053, Miaoli, Taiwan

[3] Natl Museum Marine Biol & Aquarium, Pingtung 944401, Taiwan

[4] Natl Tsing Hua Univ, Inst Biotechnol, Hsinchu 30013, Taiwan

[5] Natl Hlth Res Inst, Natl Inst Infect Dis & Vaccinol, Zhunan 35053, Miaoli, Taiwan

[6] Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 804201, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2025年 / 68卷 / 05期

关键词：

BRIARANE DITERPENOIDS; ACTIVATION; INFECTION; PROTEINS; ROUTE;

D O I：

10.1021/acs.jmedchem.4c02665

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pharmacological inhibition of the cGAS-STING-controlled innate immune pathway is an emerging therapeutic strategy for a myriad of inflammatory diseases. Here, we report GHN105 as an orally bioavailable covalent STING inhibitor. Late-stage diversification of the briarane-type diterpenoid excavatolide B allowed the installation of solubility-enhancing functional groups while enhancing its activity as a covalent STING inhibitor against multiple human STING variants, including the S154 variant responsible for a genetic autoimmune disease. Selectively engaging the membrane-proximal Cys91 residue of STING, GHN105 dose-dependently inhibited cGAS-STING signaling and type I interferon responses in cells and in vivo. Moreover, orally administered GHN105 exhibited on-target engagement in vivo and markedly reversed key pathological features in a delayed treatment of the acute colitis mouse model. Our study provided proof of concept that the synthetic briarane analog GHN105 serves as a safe, site-selective, and orally active covalent STING inhibitor and devises a regimen that allows long-term systemic administration.

引用

页码：5471 / 5487

页数：17