Discovery of environment-sensitive fluorescent ligands for SHP2 imaging in living cells and tumor sections.

SHP2, a non-receptor protein tyrosine phosphatase, is a key regulator of the cellular signal transduction pathways. Its dysregulation has been associated with the pathogenesis of various diseases, notably cancers. In this study, we developed a series of small-molecule fluorescent probes targeting the allosteric site of SHP2 for the first time, which resulted in high affinity and specific SHP2 binding. These probes exhibited a significant Stokes shift, which was crucial for minimizing the phototoxicity and ensuring superior imaging quality. SHP-PS2, the top-performing probe, exhibited an IC50 of 2.88 μmol/L against SHP2 and a Kd of 1.85 μmol/L in binding studies, with accurate SHP2 localization in living cells and tumor sections. These probes were straightforward to use and were effective tools for conveniently detecting SHP2, which had the potential to advance research in SHP2-related molecular pharmacology and drug discovery.