Medicinal Chemistry of Anti-tumor Agents Targetd at Stromal Complex V

• Project/Area Number: 20K06956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: Watanabe Takumi 公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (80270544)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん・間質相互作用 / 全合成 / 天然物 / 医薬化学 / complex V / がんー間質相互作用 / 抗がん剤 / 構造活性相関 / がん－間質相互作用 / 抗がん剤リード / ペプチド系天然物 / 呼吸鎖阻害剤 / がん分子標的薬

Outline of Research at the Start

これまで，ペプチド系天然物ロイシノスタチンAの関連物質が，がん－間質相互作用に干渉しがん細胞の増殖を抑制すること，すなわち間質のミトコンドリア電子伝達系complex Vの阻害を介し，間質細胞のIGF-I分泌を抑制し，当該活性を示すことを明らかにしてきた．本研究は当該知見を活用し，complex V阻害活性を指標とした構造活性相関SAR研究の実施，in vivo評価を経た開発候補化合物の選定，難治性がんに対する適用範囲拡大の検討とがん分子標的としてのcomplex Vの有用性評価，を基軸とした新しい作用機序の抗がん剤リード創製を目指す．

Outline of Final Research Achievements

It was found that leucinostatin A acts on complex V of prostate stromal cells co-cultured with prostate tumor cells to inhibit exhibition of IGF-1. It proved that complex V from stromal cells can be a good target of antitumor agents.
Changing an unnatural amino acid residue of leucinostatin A, AHMOD, maintained its biological activity. However, it was suggested that the alteration of the side chain structure resulted in changes of topology of whole main chain structure of the peptide to make it bind to different position of the target enzyme from that for leucinostatin A.

Academic Significance and Societal Importance of the Research Achievements

がん化学療法の分野においては現在，分子標的薬と抗体医薬が大きな成功を収めている。いずれもがん細胞に特徴的な標的をもつもので，従来の細胞毒と比較し優れた治療成績と良好なQOLをもたらしている。一方、がん組織に存在する正常細胞もがん細胞の増殖に関与していることも知られており、これが新しい抗がん剤の標的になればがん細胞の遺伝子不安定性に由来する容易な耐性獲得が回避される可能性があるとされてきた。本研究では正常細胞のcomplex Vが抗がん剤の標的になりうることを示唆するに至り、将来的な新しいがん化学療法の方法論の構築に結び付く可能性がある点で意義をもつ。

Research Products

• [Journal Article] Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment (2021)
  • Author(s): J. Yoshida, T. Ohishi, H. Abe, S. Ohba, H. Inoue, I. Usami, M. Amemiya, R. Oriez, C. Sakashita, S. Dan, M. Sugawara, T. Kawaguchi, J. Ueno, Y. Asano, A. Ikeda, M. Takamatsu, G. Amori, Y. Kondoh, K. Honda, H. Osada, T. Noda, T. Watanabe, T. Shimizu, M. Shibasaki and M. Kawada
  • Journal Title: iScience Volume: 24 Issue: 12 Pages: 103497-103497
  • DOI: 10.1016/j.isci.2021.103497
  • Peer Reviewed / Open Access
• [Journal Article] Catalytic asymmetric total synthesis of leucinostatin A. (2021)
  • Author(s): T. Watanabe, H. Abe, M. Shibasaki
  • Journal Title: Chem. Rec. Volume: 21 Issue: 1 Pages: 175-187
  • DOI: 10.1002/tcr.202000108
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of mitochondria ATP synthase suppresses prostate cancer growth through reduced insulin-like growth factor-1 secretion by prostate stromal cells (2020)
  • Author(s): Tomokazu Ohishi, Hikaru Abe, Chiharu Sakashita, Uzma Saqib, Mirza S. Baig, Shun‐ichi Ohba, Hiroyuki Inoue, Takumi Watanabe, Masakatsu Shibasaki, Manabu Kawada
  • Journal Title: Int. J. Cancer Volume: 146 Issue: 12 Pages: 3474-3484
  • DOI: 10.1002/ijc.32959
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Chemistry and biology of antitumor quinolones, intervenolin and related compounds: structure-activity relationship, inhibitory activity toward mitochondrial complex I, and in vivo efficacy (2022)
  • Author(s): Takumi Watanabe, Hikaru, Abe, Manabu Kawada, Junjiro Yoshida, Chiharu Sakashita, Shun-ichi Ohba, Hiroyuki Inoue, Tomokazu Ohishi, Masakatsu Shibasaki
  • Organizer: 37th ACS NMCS
  • Int'l Joint Research
• [Presentation] ミトコンドリアcomplex I阻害剤による細胞内外の酸性化を介した新規抗がんメカニズム (2022)
  • Author(s): 吉田潤次郎、雨宮昌秀、立田大輔、大石智一、大庭俊一、井上裕幸、阿部 光、旦 慎吾、野田哲生、渡辺 匠、清水孝雄、柴﨑正勝、川田 学
  • Organizer: 第26回 日本がん分子標的治療学会学術集会
• [Presentation] Mitochondrial complex I inhibitors suppress tumor growth through intra- and extracellular acidification (2022)
  • Author(s): Junjiro Yoshida, Tomokazu Ohishi, Hikaru Abe, Shun-ichi Ohba, Hiroyuki Inoue, Ihomi Usami, Masahide Amemiya, Raphael Oriez, Takumi Watanabe, Takao Shimizu, Masakatsu Shibasaki, Manabu Kawada
  • Organizer: The 26th JFCR-ISCC
  • Int'l Joint Research
• [Presentation] Chemical biology of leucinostatin A and its analogs, modulators of tumor-stroma interaction. (2021)
  • Author(s): Abe H,; Kawada, M.; Ohishi, T.; Sakashita, C.; Saqib, U.; Baig, M. S.; Ohba, S.; Inoue, H.; Watanabe, T.; Shibasaki, M.
  • Organizer: AIMECS2021
  • Int'l Joint Research
• [Presentation] 生物活性天然物の触媒的不斉合成研究 (2021)
  • Author(s): 渡辺 匠
  • Organizer: 第65回日本薬学会関東支部大会
  • Invited
• [Presentation] ミトコンドリアcomplex I 阻害剤による細胞内外の酸性化を介した新規抗がん活性 (2021)
  • Author(s): 吉田潤次郎，雨宮昌秀，立田大輔，大石智一，大庭俊一，井上裕幸，阿部 光，Raphael Oriez，渡辺 匠，柴崎正勝，川田 学
  • Organizer: 第25回日本がん分子標的治療学会学術集会
• [Remarks] IMC 微生物化学研究所
  • URL: https://www.bikaken.or.jp/
• [Remarks] IMC 微生物化学研究所