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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Ligands
  • Receptors, Antigen, T-Cell