Development of compound evaluation system based on pathway analysis using proteome analysis

• Project/Area Number: 17K07783
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bioorganic chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Muroi Makoto 国立研究開発法人理化学研究所, 環境資源科学研究センター, 専任研究員 (30261168)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 阻害剤 / 標的分子 / 代謝 / インフォマティクス / プロテオーム / プロテオミクス / 標的同定 / proteome / drug target / chemicalbiology / ケミカルバイオロジー / プロファイリング / 分子標的

Outline of Final Research Achievements

Compounds affecting cancer metabolism are expected to contribute to the elucidation of the mechanism of cancer metabolism and a discover of such compounds may leads to the creation of new anticancer drugs. A study was conducted for the purpose of constructing a metabolic inhibitor evaluation analysis system by improving ChemProteoBase, which is a drug target analysis system using proteomic analysis by 2D-DIGE. An improved system was developed to evaluate the effect of inhibitors on metabolism by analyzing the expression level of the spots relating cancer metabolism such as glycolytic enzyme proteins, and targets of novel compounds were clarified.

Academic Significance and Societal Importance of the Research Achievements

様々なスクリーニングで取得された生理活性物質の標的を同定することは、抗がん剤をはじめ新しい薬の開発につながる他、その過程に関与する新しい生命現象の解析に役立つ。しかし、標的を同定することは容易ではなく、様々な手法が開発されてきた。本研究の２次元電気泳動を用いたプロテオーム解析に基づく代謝阻害剤評価解析システムを用いることによって、がんを標的とした作用未知の化合物の迅速な作用解析が行えることが期待され、薬学、応用微生物学、天然物化学の研究進展にも寄与できると考えられる。

Research Products

• [Int'l Joint Research] マックス・プランク研究所(ドイツ)
• [Int'l Joint Research] 浙江大学(中国)
• [Int'l Joint Research] マックスプランク研究所(ドイツ)
• [Journal Article] Measurement of ATPase Activity of Valosin-containing Protein/p97 (2020)
  • Author(s): Suvarna Kruthi、Honda Kaori、Muroi Makoto、Kondoh Yasumitsu、Osada Hiroyuki、Watanabe Nobumoto
  • Journal Title: BIO-PROTOCOL Volume: 10 Issue: 3
  • DOI: 10.21769/bioprotoc.3516
  • Peer Reviewed / Open Access
• [Journal Article] Identification of Target Protein for Bio-active Small Molecule Using Photo-cross Linked Beads and MALDI-TOF Mass Spectrometry (2020)
  • Author(s): Suvarna Kruthi、Honda Kaori、Muroi Makoto、Kondoh Yasumitsu、Watanabe Nobumoto、Osada Hiroyuki
  • Journal Title: BIO-PROTOCOL Volume: 10 Issue: 3
  • DOI: 10.21769/bioprotoc.3517
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a Small Compound Targeting PKM2-Regulated Signaling Using 2D Gel Electrophoresis-Based Proteome-wide CETSA (2020)
  • Author(s): Nagasawa Ikuko、Muroi Makoto、Kawatani Makoto、Ohishi Tomokazu、Ohba Shun-ichi、Kawada Manabu、Osada Hiroyuki
  • Journal Title: Cell Chemical Biology Volume: 27 Issue: 2 Pages: 1-11
  • DOI: 10.1016/j.chembiol.2019.11.010
  • Peer Reviewed
• [Journal Article] Structure characterization and action mechanism of an antiaging new compound from Gastrodia elata Blume. (2019)
  • Author(s): Farooq U, Pan Y, Lin Y, Wang Y, Osada H, Xiang L, Qi J.
  • Journal Title: Oxid Med Cell Longev Volume: 2019 Pages: 5459862-5459862
  • DOI: 10.1155/2019/5459862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel inhibitor of tumorspheres reveals the activation of the serine biosynthetic pathway upon mitochondrial inhibition. (2019)
  • Author(s): Subedi A, Muroi M, Futamura Y, Kawamura T, Aono H, Nishi M, Ryo A, Watanabe N, Osada H.
  • Journal Title: FEBS Lett. Volume: 593 Issue: 8 Pages: 763-776
  • DOI: 10.1002/1873-3468.13361
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 3β,23,28-Trihydroxy-12-oleanene 3β-caffeate from Desmodium sambuense-induced neurogenesis in PC12 cells mediated by ER stress and BDNF-TrkB signaling pathways. (2019)
  • Author(s): Cheng L, Muroi M, Cao S, Bian L, Osada H, Xiang L, Qi J
  • Journal Title: Mol Pharm Volume: 16 Issue: 4 Pages: 1423-1432
  • DOI: 10.1021/acs.molpharmaceut.8b00939
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A small-molecule ligand of valosin-containing protein/p97 inhibits cancer cell-accelerated fibroblast migration. (2019)
  • Author(s): Suvarna K, Honda K, Muroi M, Kondoh Y, Osada H, Watanabe N
  • Journal Title: J Biol Chem Volume: 294 Issue: 9 Pages: 2988-2996
  • DOI: 10.1074/jbc.ra118.004741
  • Peer Reviewed / Open Access
• [Journal Article] Bioenergetic and proteomic profiling to screen small molecule inhibitors that target cancer metabolisms. (2019)
  • Author(s): Futamura Y, Muroi M, Aono H, Kawatani M, Hayashida M, Sekine T, Nogawa T, Osada H.
  • Journal Title: Biochim Biophys Acta Proteins Proteom. Volume: 1867 Issue: 1 Pages: 28-37
  • DOI: 10.1016/j.bbapap.2018.06.001
  • Peer Reviewed
• [Journal Article] Proteomic profiling for target identification of biologically active small molecules using 2D DIGE. (2018)
  • Author(s): Muroi M, Osada H.
  • Journal Title: Systems Chemical Biology (Ziegler S. and Waldmann H. eds.): Methods and Protocols, Methods in Molecular Biology Volume: 1888 Pages: 127-139
  • DOI: 10.1007/978-1-4939-8891-4_7
  • ISBN: 9781493988907, 9781493988914
• [Journal Article] Phenotypic identification of a novel autophagy inhibitor chemotype targeting lipid kinase VPS34 (2017)
  • Author(s): Robke L, Laraia L, Carnero Corrales MA, Konstantinidis G, Muroi M, Richters A, Winzker M, Engbring T, Tomassi S, Watanabe N, Osada H, Rauh D, Waldmann H, Wu YW, Engel J
  • Journal Title: Angew Chem Int Ed Engl Volume: 56 Issue: 28 Pages: 8153-8157
  • DOI: 10.1002/anie.201703738
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Allantopyrone A activates the Keap1-Nrf2 pathway and protects from oxidative stress-induced cell death in PC12 cells (2017)
  • Author(s): Shota Uesugi, Makoto Muroi, Yasumitsu Kondoh, Yoshihito Shiono, Hiroyuki Osada, Ken-ichi Kimura
  • Journal Title: The Journal of Antibiotics Volume: 70 Issue: 4 Pages: 429-434
  • DOI: 10.1038/ja.2016.99
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Development of a terpenoid-production platform in Streptomyces reveromyceticus SN-593 (2017)
  • Author(s): Khalid A、Takagi H、Panthee S、Muroi M、Chappell J、Osada H、Takahashi S
  • Journal Title: ACS Synthetic Biology Volume: 6 Issue: 12 Pages: 2339-2349
  • DOI: 10.1021/acssynbio.7b00249
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 2DE-CETSAを用いたPKM2制御シグナルに作用する化合物NPD10084の同定 (2020)
  • Author(s): 室井 誠、永澤 生久子、小川 直子、川谷 誠、大石 智一、大庭 俊一、川田 学、長田 裕之
  • Organizer: 日本農芸化学会2020年度大会
  • Int'l Joint Research
• [Presentation] Target identification of bioactive small molecules based on proteomic analyses using 2-D DIGE. (2019)
  • Author(s): Makoto Muroi, Ikuko Nagasawa, Naoko Ogawa, Harumi Aono, Yushi Futamura, Makoto Kawatani, Hiroyuki Osada
  • Organizer: RIKEN-Max Planck Joint Research Center for System Chemical Biology 7th Symposium
  • Int'l Joint Research
• [Presentation] Development of 2DE-CETSA as a novel platform by 2- dimensional electrophoresis based-proteomic analysis for target identification of small molecules (2019)
  • Author(s): Ikuko Nagasawa, Makoto Muroi, Ayumi Ikeno, Naoko Ogawa, Makoto Kawatani, Hiroyuki Osada
  • Organizer: The 1st International Symposium on Chemical Communication (ISCC2019)
  • Int'l Joint Research
• [Presentation] ２次元電気泳動を用いた化合物に相互作用するたんぱく質の解析法（2DE-CETSA）の開発 (2019)
  • Author(s): 室井 誠、永澤 生久子、池野 あゆみ、小川 直子、川谷 誠、長田 裕之
  • Organizer: 日本農芸化学会2019年度大会
• [Presentation] ChemProteoBaseを用いたMTH1阻害剤の作用解析 (2017)
  • Author(s): 室井 誠、川谷 誠、河村 達郎、近藤 恭光、二村 友史、田中 美帆、青野 晴美、本田 香織、長田 裕之
  • Organizer: 日本農芸化学会2017年度大会
• [Presentation] ChemProteoBase を用いた化合物のオフターゲット解析 (2017)
  • Author(s): 室井 誠、川谷 誠、河村 達郎、近藤 恭光、二村 友史、田中 美帆、青野 晴美、本田 香織、長田 裕之
  • Organizer: 日本ケミカルバイオロジー学会 第12回年会
• [Presentation] 表現型データベースを用いた生理活性物質の標的分子解析 (2017)
  • Author(s): 室井 誠
  • Organizer: 日本農芸化学会 2017年度 東北支部 支部大会
  • Invited
• [Book] 医薬品開発におけるオミクス解析技術 ～ゲノム・トランスクリプトーム・プロテオーム・メタボローム～ (2020)
  • Author(s): 鎌田 真由美, 奥野 恭史, 山田 弘, 森田 英利, 田丸 浩, 伊藤 昌可, 林崎 良英, 飯塚 朋代, 小林 巧, 池尾 一穂, 中岡 慎治, 松田 史生, 室井 誠, 小川 直子, 長田 裕之, 三浦 信明, 杉本 昌弘, 中山 泰宗, 三枝 淳, 松本 光晴, 久保田 浩行, 金井 弥栄, 津田 昇, 鈴木 孝昌
  • Total Pages: 181
  • Publisher: 情報機構
  • ISBN: 9784865021844
• [Remarks] 理化学研究所 環境資源科学研究センター ケミカルバイオロジー研究グループ
  • URL: http://www.cbrg.riken.jp/csrs/ja/