Mechanistic studies of tumor cell growth using marine natural product and its application for anti-tumor drug discovery

• Project/Area Number: 18K05363
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Ritsumeikan University
• Principal Investigator: Kotoku Naoyuki 立命館大学, 薬学部, 准教授 (20362618)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 海洋天然物 / ガン細胞増殖メカニズム / 作用機序解明 / 細胞内ラベル化 / 抗ガン剤 / 抗がん剤

Outline of Final Research Achievements

We have previously disclosed that the inhibition of EXD3, one of the target proteins of arenastatin A, leads to the selective growth inhibition against tumor cells. To investigate the precise role of EXD3 in the tumor cells, selective intracellular labeling of EXD3 using photoaffinity probe derived from arenastatin A is needed, and various analogues of arenastatin A were prepared for analyzing its structure-activity relationship. Through cytotoxic evaluation against some cell lines, the essential substructure for binding to EXD3 and the effective conformation for exhibiting cytotoxicity were disclosed. These findings might be useful for designing the effective affinity probe molecule to analyze the role of EXD3 in the future.

Academic Significance and Societal Importance of the Research Achievements

既存の抗ガン剤の多くは正常細胞の増殖にも影響を与えるため、重篤な副作用を引き起こす原因となっていることから、ガン細胞選択的な薬効を示す治療薬の開発は急務である。本研究成果をさらに発展させることで、新たな作用機序を有する、ガン細胞選択的な増殖抑制効果を示す治療薬の創出につながることが期待される。また、EXD3に関する研究から、ガン細胞と正常細胞の増殖メカニズムの相違点を解明できれば、さらに有効な治療法の確立へと発展する可能性があるため、本研究のさらなる推進は学術的、社会的意義の大きいものであると考える。

Research Products

• [Journal Article] Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain (2020)
  • Author(s): Masato Tanuma, Atsushi Kasai, Kazuki Bando, Naoyuki Kotoku, Kazuo Harada, Masafumi Minoshima, Kosuke Higashino, Atsushi Kimishima, Masayoshi Arai, Yukio Ago, Kaoru Seiriki, Kazuya Kikuchi, Satoshi Kawata, Katsumasa Fujita, Hitoshi Hashimoto
  • Journal Title: JCI Insight Volume: 5 Issue: 6
  • DOI: 10.1172/jci.insight.133348
  • Peer Reviewed / Open Access
• [Journal Article] Structure–Activity Relationship of Biakamide, Selective Growth Inhibitors under Nutrient-Starved Condition from Marine Sponge (2019)
  • Author(s): Ryosuke Ishida, Hirokazu Matsumoto, Sayaka Ichii, Motomasa Kobayashi, Masayoshi Arai, Naoyuki Kotoku
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 67 Issue: 3 Pages: 210-223
  • DOI: 10.1248/cpb.c18-00587
  • NAID: 130007606467
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2019-03-01
  • Peer Reviewed
• [Presentation] Synthesis and biological evaluation of novel analogs of arenastatin A by late-stage functionalization (2021)
  • Author(s): Kohei Hatta, Maho Kishimoto, Yurina Mihara, Naoyuki Kotoku
  • Organizer: AIMECS2021
  • Int'l Joint Research
• [Presentation] In vivo imaging of alkynylated S-citalopram using surface-enhanced Raman scattering (2019)
  • Author(s): Tanuma, M.; Kasai, A.; Bando, K.; Kotoku, N.; Higashino, K.; Ago, Y.; Kawata, S.; Fujita, K.; Hashimoto, H.
  • Organizer: SfN Neuroscience 2019
  • Int'l Joint Research
• [Presentation] Synthesis and Evaluation of Novel Analogs of Arenastatin A (2019)
  • Author(s): Fujimoto, K.; Kishimoto, M.; Nakamura, S.; Nakanishi, I.; Kotoku, N.
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Arenastatin Aの新規誘導体の合成研究 (2019)
  • Author(s): 藤本晃規、岸本真歩、古徳直之
  • Organizer: 日本薬学会第139年会