First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

• Published in: Science translational medicine Vol. 8; no. 370; p. 370ra184
• Main Authors: Borroto, Aldo, Reyes-Garau, Diana, Jiménez, M Angeles, Carrasco, Esther, Moreno, Beatriz, Martínez-Pasamar, Sara, Cortés, José R, Perona, Almudena, Abia, David, Blanco, Soledad, Fuentes, Manuel, Arellano, Irene, Lobo, Juan, Heidarieh, Haleh, Rueda, Javier, Esteve, Pilar, Cibrián, Danay, Martinez-Riaño, Ana, Mendoza, Pilar, Prieto, Cristina, Calleja, Enrique, Oeste, Clara L, Orfao, Alberto, Fresno, Manuel, Sánchez-Madrid, Francisco, Alcamí, Antonio, Bovolenta, Paola, Martín, Pilar, Villoslada, Pablo, Morreale, Antonio, Messeguer, Angel, Alarcon, Balbino
• Format: Journal Article
• Language: English
• Published: United States 21-12-2016
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents - pharmacology; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Cell Proliferation; Cytokines - metabolism; Drug Design; Female; Healthy Volunteers; Humans; Immunosuppression; Inhibitory Concentration 50; Ligands; Lymphocyte Activation; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred C57BL; Protein Domains; Receptors, Antigen, T-Cell - antagonists & inhibitors; Receptors, Antigen, T-Cell - immunology; Signal Transduction; Surface Plasmon Resonance; T-Lymphocytes - cytology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aaf2140

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC
(median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases.