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Peer-reviewedCC BY-NC-NDActa pharmaceutica Sinica. B

Discovery of a potent covalent inhibitor for the treatment of sepsis targeting DNAJC9: Identification of a druggable target for inflammation.

  • Xingjun Li1
  • Tao Yang2,3
  • Hui Huang1,4
  • Yalan Ma2,5
  • Lu Liu1,6
  • Qingqing Li7
  • Naixia Zhang2,5
  • Zhizhen Hui5
  • Yazhou Li1,4
  • Fang Bai6
  • Qiangqiang Chen5
  • Jiang Wang1,8
4 more authors
  • Chen Zhou2
  • Hu Zhou1,3,4
  • Wei Tang2,3
  • Hong Liu1,3,4,5,6
8 affiliations
  1. 1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  2. 2State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  3. 3University of Chinese Academy of Sciences, Beijing 100049, China.
  4. 4School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  5. 5School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  6. 6Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  7. 7Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, China.
  8. 8Lingang Laboratory, Shanghai 200031, China.
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Abstract

Sepsis is a leading cause of mortality among patients in intensive care units (ICUs), with no specific treatments for sepsis available in clinical practice. In this study, we report the discovery of compound A12, a tanshinone derivative featuring a covalent warhead, which demonstrates potent anti-inflammatory effects both in vitro and in vivo. In a lipopolysaccharide-induced mouse model of endotoxemia and acute systemic inflammation, A12 significantly reduces levels of TNF-α, IL-6, and IL-12. Distinct from current anti-inflammatory small molecules, A12 presents a unique mechanism, covalently binding to DNAJC9, thereby modulating the HSP complex and inhibiting the downstream inflammatory response. This work represents the first application of covalent drug design principles to the structural modification of the natural product tanshinone, and reveals the previously unrecognized role of DNAJC9 in inflammatory diseases, offering a novel therapeutic target for management of sepsis-associated acute systemic inflammation.

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Cite

BibTeXRIS
BibTeX
@article{li2026discovery,
  title = {{Discovery of a potent covalent inhibitor for the treatment of sepsis targeting DNAJC9: Identification of a druggable target for inflammation.}},
  author = {Xingjun Li and Tao Yang and Hui Huang and Yalan Ma and Lu Liu and Qingqing Li and Naixia Zhang and Zhizhen Hui and Yazhou Li and Fang Bai and Qiangqiang Chen and Jiang Wang and Chen Zhou and Hu Zhou and Wei Tang and Hong Liu},
  journal = {Acta pharmaceutica Sinica. B},
  year = {2026},
  month = jun,
  doi = {10.1016/j.apsb.2026.06.042},
  url = {https://europepmc.org/article/MED/42948689},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Discovery of a potent covalent inhibitor for the treatment of sepsis targeting DNAJC9: Identification of a druggable target for inflammation.
AU  - Xingjun Li
AU  - Tao Yang
AU  - Hui Huang
AU  - Yalan Ma
AU  - Lu Liu
AU  - Qingqing Li
AU  - Naixia Zhang
AU  - Zhizhen Hui
AU  - Yazhou Li
AU  - Fang Bai
AU  - Qiangqiang Chen
AU  - Jiang Wang
AU  - Chen Zhou
AU  - Hu Zhou
AU  - Wei Tang
AU  - Hong Liu
PY  - 2026
DA  - 2026/06/24
JO  - Acta pharmaceutica Sinica. B
DO  - 10.1016/j.apsb.2026.06.042
UR  - https://europepmc.org/article/MED/42948689
AB  - Sepsis is a leading cause of mortality among patients in intensive care units (ICUs), with no specific treatments for sepsis available in clinical practice. In this study, we report the discovery of compound A12, a tanshinone derivative featuring a covalent warhead, which demonstrates potent anti-inflammatory effects both in vitro and in vivo. In a lipopolysaccharide-induced mouse model of endotoxemia and acute systemic inflammation, A12 significantly reduces levels of TNF-α, IL-6, and IL-12. Distinct from current anti-inflammatory small molecules, A12 presents a unique mechanism, covalently binding to DNAJC9, thereby modulating the HSP complex and inhibiting the downstream inflammatory response. This work represents the first application of covalent drug design principles to the structural modification of the natural product tanshinone, and reveals the previously unrecognized role of DNAJC9 in inflammatory diseases, offering a novel therapeutic target for management of sepsis-associated acute systemic inflammation.
SN  - 2211-3835
SN  - 2211-3843
ER  -