|
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 |
|