Characterization of the SHP2-Fumosorinone interaction using biochemical and computational approaches
Jun Zhang1, Lei Li2, Ning Yang2
1College of Life Sciences, Institute of Life Science and Green Development and Hebei Innovation Center for Bioengineering and Biotechnology, Hebei University, Baoding, China; State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology; Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency; School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China.
Abstract:
Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) is a central modulator of proliferative signaling pathways in diverse malignancies and an important regulator of the tumor microenvironment. Owing to this dual role, SHP2 has emerged as a multifaceted target in cancer therapy. The recent discovery of several SHP2-specific inhibitors has renewed interest in this phosphatase and overturned the long-standing notion that phosphatases are "undruggable." Here, we identify Fumosorinone (FU), a secondary metabolite from Isaria fumosorosea, as a potent non-competitive inhibitor of SHP2. Enzymatic assays showed that FU inhibits full-length SHP2 with an IC50 of 38 μM, but FU's effect on the isolated catalytic (PTP) domain and observed a markedly enhanced inhibition (IC50 = 1.4 μM), suggesting that the N-terminal SH2 domains hinder FU access in the full-length enzyme. Isothermal titration calorimetry (ITC) confirmed FU's direct binding to the PTP domain, yielding dissociation constants consistent with enzymatic inhibition data. Molecular docking further indicated that FU engages a pocket formed by α4 and α7 helices on the PTP surface, exerting an allosteric inhibitory effect. Collectively, these results define the likely binding site and mode of action of FU on SHP2, providing a molecular basis for its regulatory effect and a foundation for the development of new SHP2-targeting anticancer agents.
Insights
Fumosorinone (FU) is a novel, potent inhibitor of Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2). This natural compound directly binds to SHP2, offering a new avenue for developing targeted cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- SHP2 phosphatase is a key regulator of cancer cell proliferation and the tumor microenvironment.
- SHP2 is a validated therapeutic target in oncology, with recent development of specific inhibitors.
- The 'undruggable' nature of phosphatases is being challenged by novel inhibitor discoveries.
Purpose of the Study:
- To identify and characterize novel inhibitors of SHP2.
- To elucidate the mechanism of action and binding site of Fumosorinone (FU) on SHP2.
- To provide a molecular basis for developing new SHP2-targeting anticancer agents.
Main Methods:
- Enzymatic assays to determine inhibition constants (IC50) of FU against full-length SHP2 and its catalytic domain.
- Isothermal titration calorimetry (ITC) to confirm direct binding of FU to the SHP2 PTP domain.
- Molecular docking simulations to predict the binding site and mode of FU interaction.
Main Results:
- Fumosorinone (FU) inhibits full-length SHP2 (IC50 = 38 μM) and its isolated PTP domain (IC50 = 1.4 μM).
- Enhanced inhibition of the PTP domain suggests SH2 domains hinder FU access in the full-length enzyme.
- ITC confirmed direct FU binding to the PTP domain; molecular docking revealed an allosteric inhibitory mechanism at a pocket on the PTP surface.
Conclusions:
- Fumosorinone (FU) is a potent, non-competitive inhibitor of SHP2 with an allosteric mode of action.
- The N-terminal SH2 domains modulate FU's access to the catalytic PTP domain.
- FU's defined binding site and mechanism provide a foundation for designing novel SHP2-targeted cancer therapeutics.
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