2. Academic Validation
  3. First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

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

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. balarcon@cbm.csic.es.
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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