Identification of linderalactone as a natural inhibitor of SHP2 to ameliorate CCl4-induced liver fibrosis

Yi Zhang; Binhao Cai; Yingying Li; Ying Xu; Yuhan Wang; Lulu Zheng; Xiaochun Zheng; Lina Yin; Gaozhi Chen; Yunxiang Wang; Guang Liang; Lingfeng Chen

doi:10.3389/fphar.2023.1098463

Identification of linderalactone as a natural inhibitor of SHP2 to ameliorate CCl₄-induced liver fibrosis

Front Pharmacol. 2023 Feb 9:14:1098463. doi: 10.3389/fphar.2023.1098463. eCollection 2023.

Authors

Yi Zhang¹, Binhao Cai², Yingying Li¹, Ying Xu¹, Yuhan Wang¹, Lulu Zheng^{1

3}, Xiaochun Zheng⁴, Lina Yin¹, Gaozhi Chen², Yunxiang Wang¹, Guang Liang^{1

2}, Lingfeng Chen¹

Affiliations

¹ Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China.
² Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
³ Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, China.
⁴ Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.

Abstract

Liver fibrosis is characterised by the activation of hepatic stellate cells (HSCs) and matrix deposition. Accumulating evidence has revealed that the oncogenic protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP2) acts as a therapeutic target of fibrosis. Although several SHP2 inhibitors have reached early clinical trials, there are currently no FDA-approved drugs that target SHP2. In this study, we aimed to identify novel SHP2 inhibitors from an in-house natural product library to treat liver fibrosis. Out of the screened 800 compounds, a furanogermacrane sesquiterpene, linderalactone (LIN), significantly inhibited SHP2 dephosphorylation activity in vitro. Cross-validated enzymatic assays, bio-layer interferometry (BLI) assays, and site-directed mutagenesis were used to confirm that LIN directly binds to the catalytic PTP domain of SHP2. In vivo administration of LIN significantly ameliorated carbon tetrachloride (CCl₄)-induced HSC activation and liver fibrosis by inhibiting the TGFβ/Smad3 pathway. Thus, LIN or its derivatives could be considered potential therapeutic agents against SHP2-related diseases, such as liver fibrosis or NASH.

Keywords: Src homology 2 domain-containing phosphatase 2; high-throughput screening; linderalactone; liver fibrosis; natural products.

Grants and funding

This work was supported by the National Natural Science Foundation of China (82103999 to LC), National Natural Science Foundation of China (82073705 to GC), Natural Science Funding of Zhejiang Province (LR22H300002 to GC), Wenzhou Major Scientific and Technological Innovation Project (ZY2021023 to GC), Qianjiang Talent Plan of Zhejiang (QJD1902016 to GC), Natural Science Funding of Zhejiang Province (LQ22H300007 to LC), Zhejiang Health Program (YS2022004 to LC), and Zhejiang Medical and Health Science Project (2023KY622 to LZ).