Page 47 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

Discovery and Development of an Orally Bioavailable Covalent STING

Inhibitor Derived from a Macrocyclic Marine Diterpenoid

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Guang-Hao Niu, Wan-Chi Hsiao, Po-Hsun Lee, Li-Guo Zheng, Y u -Shao Yang, Wei-
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Cheng Huang, Chih-Chien Hsieh, Tai-Yu Chiu, Jing-Ya Wang, Ching-Ping Chen,
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Chen-Lung Huang , May-Su You , Yi-Ping Kuo , Chien-Ming Wang, Zhi-Hong Wen,
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Guann-Yi Yu, Chiung-Tong Chen, Y a -Hui Chi, Chun-Wei Tung, Shu-Ching Hsu,
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Teng-Kuang Yeh, Ping-Jyun Sung,* Mingzi Zhang,* Lun Kelvin Tsou* , 1
,2

1 Institute of Biotechnology and Pharmaceutical Research,
2 Institute of Molecular and Genomic Medicine,
3 National Institute of Infectious Diseases and Vaccinology,
National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan
4 Institute of Biotechnology, National Tsing Hua University, Hsinchu, 30013, Taiwan
5 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University,
Kaohsiung 804201, Taiwan
6 National Museum of Marine Biology and Aquarium, Pingtung 944401, Taiwan
* Email: pjsung@nmmba.gov.tw (P .-J.S.); zhangmz@nhri.edu.tw (M.Z.);
kelvintsou@nhri.edu.tw (L.K.T.)

Abstract
The emerging frontier in drug discovery targets the proteome’s “dark matter,” which includes
underexplored pathways that evade conventional therapies. Marine-derived natural products,
with their unique reactive groups and macrocyclic architectures, offer chemically novel
scaffolds to engage elusive targets. Chemoproteomics unites this potential by combining
covalent library screening and proteome-wide ligandability mapping to decode compound-
target interactions. Central to this approach, our covalent probe profiling identified excavatolide
B (excB), a marine coral-derived diterpenoid, as a covalent STING inhibitor that selectively
targets Cys91, a residue critical for STING palmitoylation and subsequent activation. Structure-
guided optimization then yielded GHN105, the first orally bioavailable covalent STING
inhibitor. Systematic SAR exploration also achieved sub-micromolar potency against gain-of-
function STING mutants, enhanced solubility, and improved pharmacokinetics. In preclinical
IBD models, oral GHN105 suppressed pathogenic interferon signaling, demonstrated in vivo

target engagement, and reversed acute colitis. This work establishes chemoproteomics as a core
methodology for targeting the “undruggable” targets, linking reactive chemotypes within the
macrocyclic briarane-type diterpenoid to functional optimization and clinical translation. By

mapping chemical space to cellular outcomes, this strategy should accelerate the development
of selective, new therapeutic means against underexplored disease pathways.

Keywords: cGAS-STING; Marine natural product; Macrocyclic briarane-type diterpenoid;
Late-stage diversification; Orally bioavailable; Covalent inhibitor

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