PMID- 36843936
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230228
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 14
DP  - 2023
TI  - Identification of linderalactone as a natural inhibitor of SHP2 to ameliorate 
      CCl(4)-induced liver fibrosis.
PG  - 1098463
LID - 10.3389/fphar.2023.1098463 [doi]
LID - 1098463
AB  - 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 (CCl(4))-induced HSC activation and liver 
      fibrosis by inhibiting the TGFbeta/Smad3 pathway. Thus, LIN or its derivatives could 
      be considered potential therapeutic agents against SHP2-related diseases, such as 
      liver fibrosis or NASH.
CI  - Copyright (c) 2023 Zhang, Cai, Li, Xu, Wang, Zheng, Zheng, Yin, Chen, Wang, Liang 
      and Chen.
FAU - Zhang, Yi
AU  - Zhang Y
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Cai, Binhao
AU  - Cai B
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, Zhejiang, China.
FAU - Li, Yingying
AU  - Li Y
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Xu, Ying
AU  - Xu Y
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Wang, Yuhan
AU  - Wang Y
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Zheng, Lulu
AU  - Zheng L
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
AD  - Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 
      China.
FAU - Zheng, Xiaochun
AU  - Zheng X
AD  - Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated 
      People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
FAU - Yin, Lina
AU  - Yin L
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Chen, Gaozhi
AU  - Chen G
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, Zhejiang, China.
FAU - Wang, Yunxiang
AU  - Wang Y
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
FAU - Liang, Guang
AU  - Liang G
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
AD  - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou 
      Medical University, Wenzhou, Zhejiang, China.
FAU - Chen, Lingfeng
AU  - Chen L
AD  - Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou 
      Medical College, Hangzhou, Zhejiang, China.
LA  - eng
PT  - Journal Article
DEP - 20230209
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9946977
OTO - NOTNLM
OT  - Src homology 2 domain-containing phosphatase 2
OT  - high-throughput screening
OT  - linderalactone
OT  - liver fibrosis
OT  - natural products
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/02/28 06:00
MHDA- 2023/02/28 06:01
PMCR- 2023/02/09
CRDT- 2023/02/27 04:00
PHST- 2022/11/15 00:00 [received]
PHST- 2023/01/27 00:00 [accepted]
PHST- 2023/02/27 04:00 [entrez]
PHST- 2023/02/28 06:00 [pubmed]
PHST- 2023/02/28 06:01 [medline]
PHST- 2023/02/09 00:00 [pmc-release]
AID - 1098463 [pii]
AID - 10.3389/fphar.2023.1098463 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Feb 9;14:1098463. doi: 10.3389/fphar.2023.1098463. 
      eCollection 2023.