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

• 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• 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.

Research Products

• [Journal Article] CYLD and the NEMO zinc finger regulate tumor necrosis factor signaling and early embryogenesis. (2015)
  • Author(s): Zhao, Y., Ma, C. A., Wu, L., Iwai, K., Ashwell, J. D., Oltz, E. M., Ballard, D. W., and Jain, A.
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 36 Pages: 22076-22084
  • DOI: 10.1074/jbc.m115.658096
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. (2015)
  • Author(s): Bowman, J., Rodgers, M.A., Shi, M., Amatya, R., Hostager, B., Iwai, K., Gao, S.J., and Jung, J.U.
  • Journal Title: MBio. Volume: 6 Issue: 6
  • DOI: 10.1128/mbio.01777-15
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis. (2015)
  • Author(s): Matsunaga Y, Nakatsu Y, Fukushima T, Okubo H, Iwashita M, Sakoda H, Fujishiro M, Yamamotoya T, Kushiyama A, Takahashi S, Tsuchiya Y, Kamata H, Tokunaga F, Iwai K, Asano T.
  • Journal Title: Mediators Inflamm. Volume: 2015 Issue: 1 Pages: 125380-125380
  • DOI: 10.1155/2015/125380
  • Peer Reviewed / Open Access
• [Journal Article] Gliotoxin Suppresses NF-kappaB Activation by Selectively Inhibiting Linear Ubiquitin Chain Assembly Complex (LUBAC) (2015)
  • Author(s): Hiroki Sakamoto, Shinichiro Egashira, Nae Saito, Takayoshi Kirisako, Simon Miller, Yoshiteru Sasaki, Tadahiko Matsumoto, Manabu Shimonishi, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Hirotatsu Kojima, Takayoshi Okabe, Soichi Wakatsuki, Kazuhiro Iwai, Tetsuo Nagano
  • Journal Title: ACS Chemical Biology Volume: 10 Issue: 3 Pages: 675-681
  • DOI: 10.1021/cb500653y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://mcp.med.kyoto-u.ac.jp/
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://www.mcp.med.kyoto-u.ac.jp/