Study on chemical biology for protein SUMOylation

2013 Fiscal Year Final Research Report

• Project/Area Number: 23510288
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical biology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: ITO Akihiro 独立行政法人理化学研究所, 吉田化学遺伝学研究室, 専任研究員 (40391859)
• Co-Investigator(Renkei-kenkyūsha): HIRAI Go 独立行政法人理化学研究所, 袖岡有機合成化学研究室, 専任研究員 (50359551)
• Project Period (FY): 2011 – 2013
• Keywords: SUMO / 阻害剤 / 抗がん剤 / 脱SUMO化酵素

Research Abstract

The aim of this study is to elucidate roles of protein SUMOylation in carcinogenesis using a chemical biology approach. Using an in situ cell-based SUMOylation assay system, we identified several small molecule inhibitors of SUMOylation including spectomycin B1 as SUMO E2 (Ubc9) inhibitor. Our findings suggested that Ubc9 inhibitors such as spectomycin B1 have a potential as a therapeutic agent against ERalpha-dependent breast cancers. Furthermore, we identified a novel deSUMOylatuon enzyme, SENP1, inhibitor by an in situ deSUMOylation assay. We found that SENP1 inhibitor reduced the activity of HIF-1alpha,an important transcriptional factor for cancer survival under hypoxia microenvironment. In addition, we succeeded in developing novel assay systems for detecting non-covalent interactions between SUMO and SIM using a split-luciferase complementation and identified first small molecules that inhibit SUMO-dependent protein-protein interactions.

Research Products

• [Journal Article] Discovery of small molecule inhibitors targeting the SUMOSIM interaction using a protein interface consensus approach (2013)
  • Author(s): Voet A#, Ito A#, Hirohama M, Yoshida M, Zhang KY. #equally contributed
  • Journal Title: Medchemcomm. Volume: in press
  • Peer Reviewed
• [Journal Article] Identification of 1, 2, 5-Oxadiazoles as a New Class of SENP2 Inhibitors Using Structure Based Virtual Screening (2013)
  • Author(s): Kumar A#, Ito A#, Takemoto M, Yoshida M, Zhang KY. #equally contributed
  • Journal Title: J. Chem. Inf. Model. Volume: 54 Pages: 870-80
  • DOI: 10.1021/ci4007134
  • Peer Reviewed
• [Journal Article] Inhibition of protein SUMOylation by davidiin, an ellagitannin from Davidia involucrate (2013)
  • Author(s): Takemoto M, Kawamura Y, Hirohama M, Yamaguchi Y, Handa H, Saitoh H, Nakao Y, Kawada M, Khalid K, Koshino H, Kimura K, Ito A, Minoru Yoshida M.
  • Journal Title: J. Antibiot. Volume: 67 Pages: 335-8
  • DOI: 10.1038/ja.2013.142
  • Peer Reviewed
• [Journal Article] Assay methods for SUMO-SIM interactions in vivo and in vitro using a split-luciferase complementation system (2013)
  • Author(s): Hirohama M, Voet AR, Ozawa T, Saitoh H, Nakao Y, Zhang KY, Ito A, Yoshida M.
  • Journal Title: Anal. Biochem. Volume: 448 Pages: 92-4
  • DOI: 10.1016/j.ab.2013.12.009
  • Peer Reviewed
• [Journal Article] Spectomycin B1 as a Novel SUMOylation Inhibitor That Directly Binds to SUMO E2 (2013)
  • Author(s): Hirohama M, Kumar A, Fukuda I, Matsuoka S, Igarashi Y, Saitoh H, Takagi M, Shin-Ya K, Honda K, Kondoh Y, Saito T, Nakao Y, Osada H, Zhang KY, Yoshida M, Ito A.
  • Journal Title: ACS Chem, Biol. Volume: 8 Pages: 2635-42
  • DOI: 10.1021/cb400630z
  • Peer Reviewed
• [Journal Article] Identification of quinazolinyloxy biaryl urea as a new class of SUMO activating enzyme 1 inhibitors (2013)
  • Author(s): Kumar A, Ito A, Hirohama M, Yoshida M, Zhang KY.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Pages: 5145-9
  • DOI: 10.1016/j.bmcl.2013.07.022
  • Peer Reviewed
• [Journal Article] Identification of sumoylation activating enzyme 1 inhibitors by structure-based virtual screening (2013)
  • Author(s): Kumar A, Ito A, Hirohama M, Yoshida M, Zhang KY.
  • Journal Title: J Chem Inf Model. Volume: 53 Pages: 809-20
  • DOI: 10.1021/ci300618e
  • Peer Reviewed
• [Presentation] タンパク質 SUMO化を標的とした化合物の同定とその抗がん活性 (2014)
  • Author(s): 伊藤昭博
  • Organizer: 新学術領域天然物ケミカルバイオロジー地区ミニシンポジウム「化学と生物学の打開策次世代天然物ケミカルバイオロジー研究の開拓へ」
  • Place of Presentation: 和光
  • Year and Date: 2014-03-01
• [Presentation] タンパク質 SUMO化を標的とした阻害剤の探索 -タンパク質SUMO化酵素阻害剤および SUMO-SIM結合阻害剤について - (2014)
  • Author(s): 伊藤昭博
  • Organizer: 第11回SUMO研究会
  • Place of Presentation: 和光
  • Year and Date: 2014-01-10
• [Presentation] タンパク質SUMO化を標的とした化合物の探索 (2013)
  • Author(s): 伊藤昭博、吉田稔
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-11
• [Presentation] 脱SUMO化酵素SENP1阻害剤の探索 (2013)
  • Author(s): 伊藤昭博、掛谷秀昭、吉田稔
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-13
• [Presentation] SUMO化・脱SUMO化阻害剤の現状 (2012)
  • Author(s): 伊藤昭博
  • Organizer: 第10回SUMO化研究会
  • Place of Presentation: 熊本
  • Year and Date: 2012-11-22
• [Presentation] SUMO E2阻害剤としてのエラグ酸の発見とがん治療薬としての可能性 (2012)
  • Author(s): 伊藤昭博、木村賢一、吉田稔
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] Spectomycin B1 suppresses Estrogen Receptor α-Dependent Breast Cancer Cell Growth by inhibiting a SUMO E2 Activity (2012)
  • Author(s): Akihiro Ito, Mikako Hirohama, Yasuhiro Igarashi, Yasumitsu Kondoh, Tamio Saito, Hiroyuki Osada, Minoru Yoshida
  • Organizer: 2nd SNU-RIKEN Joint Symposium on Chemical Biology, Chuncheon
  • Place of Presentation: Chuncheon, South Korea
  • Year and Date: 2012-05-18
• [Presentation] エラグ酸によるタンパク質SUMO化阻害 (2012)
  • Author(s): 米山操、広浜美香子、木村賢一、半田宏、伊藤昭博、吉田稔
  • Organizer: 日本農芸化学会2012年度大会
  • Place of Presentation: 京都
  • Year and Date: 2012-03-23
• [Presentation] Discovery of spectomycin B1 as a SUMO E2 inhibitor and its potential for anti-breast cancer therapy (2012)
  • Author(s): Akihiro Ito, Mikako Hirohama, Yasuhiro Igarashi, Yasumitsu Kondoh, Tamio Saito, Hiroyuki Osada, Minoru Yoshida
  • Organizer: Riken-Max Planck Joint Research Centerkick off symposium
  • Place of Presentation: Dortmund, Germany
  • Year and Date: 2012-03-06
• [Presentation] Discovery of Spectomycin B1 as a SUMO E2 Inhibitor (2012)
  • Author(s): Akihiro Ito, Mikako Hirohama, Yasuhiro Igarashi, Yasumitsu Kondoh, Tamio Saito, hiroyuki Osada, Minoru Yoshida
  • Organizer: The 6th Korean-JapanChemical Biology Symposium
  • Place of Presentation: 札幌
  • Year and Date: 2012-01-27
• [Presentation] SUMO E2阻害剤の発見 (2011)
  • Author(s): 伊藤昭博
  • Organizer: 第2回京都大学GCOE-理化学研究所共同シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2011-11-11
• [Presentation] タンパク質SUMO化を標的とした小分子化合物の探索 (2011)
  • Author(s): 伊藤昭博
  • Organizer: 第9回SUMO研究会
  • Place of Presentation: 出雲
  • Year and Date: 2011-09-30
• [Presentation] Spectomycin B1はSUMO E2を標的とする新規SUMO化阻害剤である (2011)
  • Author(s): 伊藤昭博、吉田稔
  • Organizer: 日本がん分子標的治療学会第15回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-23