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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 3 vom: 08. Feb., Seite 1949-1960 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Aziz, Faisal [VerfasserIn] |
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| Links: |
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| Themen: |
4QD397987E |
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| Anmerkungen: |
Date Completed 09.02.2024 Date Revised 25.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c01763 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Dey, Raja |e verfasserin |4 aut | |
| 700 | 1 | |a Hicks, Katherine A |e verfasserin |4 aut | |
| 700 | 1 | |a Rao, Sumitha |e verfasserin |4 aut | |
| 700 | 1 | |a Jordan, Luis Ortiz |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Emery |e verfasserin |4 aut | |
| 700 | 1 | |a Shumate, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Scampavia, Louis |e verfasserin |4 aut | |
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| 700 | 1 | |a Spicer, Timothy P |e verfasserin |4 aut | |
| 700 | 1 | |a French, Jarrod B |e verfasserin |4 aut | |
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