Increasing human Th17 differentiation through activation of orphan nuclear receptor retinoid acid-related orphan receptor γ (RORγ) by a class of aryl amide compounds.
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.
Discovery Technology and Neuroinflammation Discovery Performance Unit, GlaxoSmithKline R&D Center, Shanghai, China. wei.3.zhang@gsk.com
Wei
W
Zhang
Jing
J
Zhang
Leiping
L
Fang
Ling
L
Zhou
Shuai
S
Wang
Zhijun
Z
Xiang
Yuan
Y
Li
Bruce
B
Wisely
Guifeng
G
Zhang
Gang
G
An
Yonghui
Y
Wang
Stewart
S
Leung
Zhong
Z
Zhong
D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002942:Circular Dichroism; D017930:Genes, Reporter; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D019169:Jurkat Cells; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D061251:Primary Cell Culture; D055550:Protein Stability; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D005466:Fluorocarbons
D000577:Amides; D001549:Benzamides; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013844:Thiazoles; D014230:Triazoles; C559087:SR 1078; D005466:Fluorocarbons