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Kwon, H. Moo
Inflammation and Kidney Disorder Lab
Research Interests
  • TonEBP, Obesity, Cancer, Chronic inflammatory diseases, Brain disorder, Kidney disorders, Genomic instability

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Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhibitors

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Title
Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhibitors
Author
Han, Eun-JinKim, Hyun YoungLee, NaeunKim, Nam-HoonYoo, Seung-AhKwon, H. MooJue, Dae-MyungPark, Yune-JungCho, Chul-SooDe, Tran QuangJeong, Dea YoungLim, Hee-JongPark, Woo KyuLee, Ge HyeongCho, HeeyeongKim, Wan-Uk
Keywords
NFAT5 suppressor; κB inhibitor; Small molecules; High-throughput drug screening; Chronic arthritis
Issue Date
201704
Publisher
ELSEVIER SCIENCE BV
Citation
EBIOMEDICINE, v.18, no., pp.261 - 273
Abstract
Nuclear factor of activated T cells 5 (NFAT5) has been implicated in the pathogenesis of various human diseases, including cancer and arthritis. However, therapeutic agents inhibiting NFAT5 activity are currently unavailable. To discover NFAT5 inhibitors, a library of >. 40,000 chemicals was screened for the suppression of nitric oxide, a direct target regulated by NFAT5 activity, through high-throughput screening. We validated the anti-NFAT5 activity of 198 primary hit compounds using an NFAT5-dependent reporter assay and identified the novel NFAT5 suppressor KRN2, 13-(2-fluoro)-benzylberberine, and its derivative KRN5. KRN2 inhibited NFAT5 upregulation in macrophages stimulated with lipopolysaccharide and repressed the formation of NF-κB p65-DNA complexes in the NFAT5 promoter region. Interestingly, KRN2 selectively suppressed the expression of pro-inflammatory genes, including Nos2 and Il6, without hampering high-salt-induced NFAT5 and its target gene expressions. Moreover, KRN2 and KRN5, the latter of which exhibits high oral bioavailability and metabolic stability, ameliorated experimentally induced arthritis in mice without serious adverse effects, decreasing pro-inflammatory cytokine production. Particularly, orally administered KRN5 was stronger in suppressing arthritis than methotrexate, a commonly used anti-rheumatic drug, displaying better potency and safety than its original compound, berberine. Therefore, KRN2 and KRN5 can be potential therapeutic agents in the treatment of chronic arthritis.
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DOI
http://dx.doi.org/10.1016/j.ebiom.2017.03.039
ISSN
2352-3964
Appears in Collections:
SLS_Journal Papers
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