120th General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Exhibition Hall 2+3
Time 10월 19일 (목요일) 11:00~12:30
Code MEDI.P-328
Subject IinQ attenuates systemic inflammatory responses via selectively impairing the Myddosome complex formation upon TLR4 ligation
Authors Yunkyoung Hwang, Young Goo Kang, Byunghoon Ahn1, Hee Nam Lim2, ILL YOUNG LEE2,*
Department of Chemistry, Sungkyunkwan University, Korea
1chemistry, Korea University, Korea
2Center for Eco-Friendly New Materials, Korea Research Institute of Chemical Technology, Korea
Abstract A selective, small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-jB-mediated inflammatory disease. Brazilin was identified as a selective upstream IKK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising of brazilin analogues, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isoquinoline-3,8-dione (IinQ) with the tetracyclic skeleton of the brazilin, was identified as a selective and potent inhibitor of IRAK1-dependent NF-jB activation upon TLR4 ligation. In RAW264.7 macrophages, IinQ drastically suppressed activation of upstream IKK signaling events including membrane-bound IRAK1 ubiquitination and IKK phosphorylation by the TLR4 ligand, resulting in reduced expression of proinflammatory mediators including IL-6, TNF-a, and nitric oxide. Interestingly, IinQ did not suppress NF-jB activation via the TLR3 ligand, DNA damaging agents, or a protein kinase C activator, indicating IinQ is specific for TLR4 signaling. Analysis of upstream signaling events further confirmed that IinQ disrupts the MyD88-IRAK1-TRAF6 complex formation induced by LPS treatment, without affecting TLR4 oligomerization
E-mail dbsruddl2003@nate.com