Home Products Cited in Publications Worldwide Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins
Faisal Aziz; Kanamata Reddy; Virneliz Fernandez Vega; Raja Dey; Katherine A. Hicks; Sumitha Rao; Luis Ortiz Jordan; Emery Smith; Justin Shumate; Louis Scampavia; Nicholas Carpino; Timothy P. Spicer; Jarrod B. French
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.
2-Amino-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid HCl
2-(3,4-Dichlorobenzamido)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid
2-(2-Chlorobenzamido)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propanoic acid