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

  • Sci Transl Med. 2016 Dec 21;8(370):370ra184. doi: 10.1126/scitranslmed.aaf2140.
Aldo Borroto  1 ,  Diana Reyes-Garau  1 ,  M Angeles Jiménez  2 ,  Esther Carrasco  3 ,  Beatriz Moreno  4 ,  Sara Martínez-Pasamar  4 ,  José R Cortés  5 ,  Almudena Perona  1 ,  David Abia  1 ,  Soledad Blanco  1 ,  Manuel Fuentes  6 ,  Irene Arellano  1 ,  Juan Lobo  1 ,  Haleh Heidarieh  1 ,  Javier Rueda  1 ,  Pilar Esteve  1 ,  Danay Cibrián  5 ,  Ana Martinez-Riaño  1 ,  Pilar Mendoza  1 ,  Cristina Prieto  1 ,  Enrique Calleja  1 ,  Clara L Oeste  1 ,  Alberto Orfao  6 ,  Manuel Fresno  1 ,  Francisco Sánchez-Madrid  5 ,  Antonio Alcamí  1 ,  Paola Bovolenta  1 ,  Pilar Martín  5 ,  Pablo Villoslada  4 ,  Antonio Morreale  1 ,  Angel Messeguer  3 ,  Balbino Alarcon  7
Affiliations
  • 1. Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
  • 2. Instituto de Química Física Rocasolano, CSIC, Madrid, Spain.
  • 3. Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
  • 4. Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain.
  • 5. Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 6. Centro de Investigación del Cáncer, University of Salamanca-CSIC, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
  • 7. Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain. [email protected].
PMID: 28003549 DOI: 10.1126/scitranslmed.aaf2140
Abstract

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 IC50 (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.

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