Issue
Copyright (c) 2025 Beom Su Seo, Dong Oh Moon
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.Structure-based identification of liensinine as a natural allosteric SHP2 inhibitor with anti-proliferative activity in HepG2 cells
Corresponding Author(s) : Dong Oh Moon
Cellular and Molecular Biology,
Vol. 71 No. 12: Issue 12
Abstract
SHP2, encoded by the PTPN11 gene, is a non-receptor tyrosine phosphatase that plays a key role in oncogenic Ras/MAPK signaling. Aberrant SHP2 activity contributes to the progression of various cancers, including liver cancer. In this study, we used an AI-based virtual screening platform (HyperLab) to evaluate 127 natural compounds for SHP2 allosteric inhibition. Liensinine, a bisbenzylisoquinoline alkaloid from Nelumbo nucifera, was identified as a top candidate with strong predicted binding to the SHP2 allosteric tunnel site. This tunnel-shaped pocket is located at the interface between the N-SH2, C-SH2, and PTP domains, where allosteric inhibitors stabilize SHP2 in its closed, inactive conformation by preventing domain rearrangement. Docking analyses using HyperLab and CB-Dock2 consistently supported its interaction with key regulatory residues. Biochemical assays confirmed that Liensinine inhibits SHP2 phosphatase activity in a dose-dependent manner, with an IC₅₀ of ~5.2 μM. In HepG2 cells, Liensinine reduced cell viability to approximately 70% at 20 μM and 50% at 50 μM, indicating a concentration-dependent cytotoxic effect. Additionally, RNA-seq data analysis revealed upregulated PTPN11 expression in hepatocellular carcinoma tissues compared to normal liver. These quantitative findings strengthen the experimental evidence for Liensinine’s inhibitory potential. Together, these findings suggest that Liensinine may serve as a natural SHP2 allosteric inhibitor with anticancer potential.
Keywords
Download Citation
Endnote/Zotero/Mendeley (RIS)BibTeX
