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

• Published in: Journal of medicinal chemistry 2024-02, Vol.67 (3), p.1949-1960
• Main Authors: Aziz, Faisal, Reddy, Kanamata, Fernandez Vega, Virneliz, Dey, Raja, Hicks, Katherine A., Rao, Sumitha, Jordan, Luis Ortiz, Smith, Emery, Shumate, Justin, Scampavia, Louis, Carpino, Nicholas, Spicer, Timothy P., French, Jarrod B.
• Format: Article
• Language: English
• Subjects: Alanine - analogs & derivatives; Enzyme Inhibitors; Histidine; Phosphoric Monoester Hydrolases - chemistry; Quinolones - pharmacology; Receptors, Antigen, T-Cell
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01763

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.