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Identification of a selective ROR gamma ligand that suppresses T(H)17 cells and stimulates T regulatory cells

Academic Article
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Overview

authors

  • Solt, Laura A.
  • Kumar, N.
  • He, Y.
  • Kamenecka, Theodore
  • Griffin, Patrick
  • Burris, Thomas

publication date

  • September 2012

journal

  • ACS Chemical Biology  Journal

abstract

  • Nuclear receptors (NRs) are ligand-regulated transcription factors, many of which are validated targets for clinical purposes. The retinoic acid receptor-related orphan nuclear receptors alpha and gamma t (ROR? and ROR?t) are considered to be the master regulators of development of T(H)17 cells, a subset of T cells that have been implicated in the pathology of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). We report here the identification of a novel ROR?-specific synthetic ligand, SR1555, that not only inhibits T(H)17 cell development and function but also increases the frequency of T regulatory cells. Our data suggests synthetic ROR? ligands can be developed that target both suppression of T(H)17 and stimulation of T regulatory cells, offering key advantages in development of therapeutics targeting autoimmune diseases.
  • Nuclear receptors (NRs) are ligand-regulated transcription factors, many of which are validated targets for clinical purposes. The retinoic acid receptor-related orphan nuclear receptors alpha and gamma t (RORα and RORγt) are considered to be the master regulators of development of T(H)17 cells, a subset of T cells that have been implicated in the pathology of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). We report here the identification of a novel RORγ-specific synthetic ligand, SR1555, that not only inhibits T(H)17 cell development and function but also increases the frequency of T regulatory cells. Our data suggests synthetic RORγ ligands can be developed that target both suppression of T(H)17 and stimulation of T regulatory cells, offering key advantages in development of therapeutics targeting autoimmune diseases.

subject areas

  • Animals
  • CD4-Positive T-Lymphocytes
  • Cell Differentiation
  • Cells, Cultured
  • Drug Discovery
  • HEK293 Cells
  • Humans
  • Interleukin-17
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Sulfonamides
  • T-Lymphocytes, Regulatory
  • Thiazoles
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Identity

PubMed Central ID

  • PMC3448878

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb3002649

PubMed ID

  • 22769242
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Additional Document Info

start page

  • 1515

end page

  • 1519

volume

  • 7

issue

  • 9

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