Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins

The suppressor of T cell receptor signaling (Sts) proteins
are
negative regulators of immune signaling. Genetic inactivation of these
proteins leads to significant resistance to infection. From a 590,000
compound high-throughput screen, we identified the 2-(1H)-quinolinone derivative, rebamipide, as a putative inhibitor of
Sts phosphatase activity. Rebamipide, and a small library of derivatives,
are competitive, selective inhibitors of Sts-1 with IC50 values from low to submicromolar. SAR analysis indicates that the
quinolinone, the acid, and the amide moieties are all essential for
activity. A crystal structure confirmed the SAR and reveals key interactions
between this class of compound and the protein. Although rebamipide
has poor cell permeability, we demonstrated that a liposomal preparation
can inactivate the phosphatase activity of Sts-1 in cells. These studies
demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated
and provide foundational tools and insights for the development of
immune-enhancing therapies that target the Sts proteins.