Abstract
In a screen for small-molecule inhibitors of retinoid acid-related orphan receptor γ (RORγ), we fortuitously discovered that a class of aryl amide compounds behaved as functional activators of the interleukin 17 (IL-17) reporter in Jurkat cells. Three of these compounds were selected for further analysis and found to activate the IL-17 reporter with potencies of ∼0.1 μM measured by EC50. These compounds were shown to directly bind to RORγ by circular dichroism-based thermal stability experiments. Furthermore, they can enhance an in vitro Th17 differentiation process in human primary T cells. As RORγ remains an orphan nuclear receptor, discovery of these aryl amide compounds as functional agonists will now provide pharmacological tools for us to dissect functions of RORγ and facilitate drug discovery efforts for immune-modulating therapies.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- ROR
- retinoid acid-related orphan receptor
- LBD
- ligand binding domain
- Th17
- T-helper 17
- IL
- interleukin
- CNS
- conserved noncoding sequence
- PBS
- phosphate-buffered saline
- SRC
- steroid receptor coactivator
- FRET
- fluorescence resonance energy transfer
- TR
- time-resolved
- APC
- allophycocyanin
- DMSO
- dimethyl sulfoxide
- T0901317
- N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide
- SR1078
- N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-4-(trifluoromethyl)benzamide
- inhibitor Y
- N-(5-benzoyl-4-phenylthiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide
- compound 1b
- N-(4,6-dimethylbenzo[d]thiazol-2-yl)-3-methylthiophene-2-carboxamide
- compound 1c
- N-(2-(4-ethylphenyl)-2H-benzo[d][1,2,3]triazol-5-yl)propionamide
- CD
- circular dichroism
- h
- human
- ELISA
- enzyme-linked immunosorbent assay
- inh%
- percentage of inhibition.
- Received March 7, 2012.
- Accepted June 14, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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