Development of small molecules inhibiting linear ubiquitin-medaited NF-kappaB actviation

2015 Fiscal Year Final Research Report

• Project/Area Number: 26670154
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: Kazuhiro wai 京都大学, 医学(系)研究科(研究院), 教授 (60252459)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: ユビキチン / NF-kappaB / LUBAC / 直鎖状ユビキチン鎖

Outline of Final Research Achievements

NF-κB is a family of transcription factor, which is involved in the pathogenesis of several malignant tumors. The liner ubiquitin chains, which is selectively generated the LUBAC ubiquitin ligase discovered by us, is known to be selectively involved in the activation of NF-κB. Thus, LUBAC-mediated linear ubiquitination is a suitable target of anti-cancer drugs. We have generated high-throughput ELISA screening system of LUBAC inhibitors using petit-SHARPIN, petit-LUBAC and anti-linear ubiquitin antibody all of that were generated by us and identified two compounds that inhibited LUBAC-mediated generation of linear chains. However, none of them can inhibited linear ubiquitination in cells. We have identified another LUBAC inhibitory compound in other study and evaluated the compound in this study. The compound Y did inhibit NF-κB activation and linear ubiquitination in cells. Moreover preliminary analyses revealed that The compound Y appeared to suppress LUBAC in mice.

Free Research Field

病態医化学