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Sci Transl Med. 2016 Dec 21;8(370):370ra184. doi: 10.1126/scitranslmed.aaf2140.

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

Author information

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.

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.

PMID:
28003549
DOI:
10.1126/scitranslmed.aaf2140
[Indexed for MEDLINE]

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