Characterization of the SHP2-Fumosorinone interaction using biochemical and computational approaches

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.