1. Academic Validation
  2. Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhibitors

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

  • EBioMedicine. 2017 Apr;18:261-273. doi: 10.1016/j.ebiom.2017.03.039.
Eun-Jin Han 1 Hyun Young Kim 2 Naeun Lee 1 Nam-Hoon Kim 1 Seung-Ah Yoo 1 H Moo Kwon 3 Dae-Myung Jue 4 Yune-Jung Park 5 Chul-Soo Cho 5 Tran Quang De 6 Dae Young Jeong 2 Hee-Jong Lim 6 Woo Kyu Park 2 Ge Hyeong Lee 2 Heeyeong Cho 7 Wan-Uk Kim 8
Affiliations

Affiliations

  • 1 Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Republic of Korea.
  • 2 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
  • 3 School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 4 Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
  • 5 Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
  • 6 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, Republic of Korea.
  • 7 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, Republic of Korea. Electronic address: [email protected].
  • 8 Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Republic of Korea; Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: [email protected].
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.

Keywords

Chronic arthritis; High-throughput drug screening; NFAT5 suppressor; Small molecules; κB inhibitor.

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