Development of novel anticancer drugs targeting for controlling the function and expression of oxidative stress-induced protein

• Project/Area Number: 24790114
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Gifu Pharmaceutical University
• Principal Investigator: ENDO Satoshi 岐阜薬科大学, 薬学部, 助教 (60433207)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: aldo-keto reductases / 抗癌剤 / 抗癌剤耐性抑制薬 / 制癌薬

Research Abstract

Aldo-keto reductases (AKR) which are induced by oxidative stress via Keap1/Nrf2 pathway are suggested to involve in proliferation and survival of cancer cells. Then, we searched novel AKR inhibitors for anticancer therapeutic development and have succeeded the development of the most potent and high selective AKR inhibitors and construction of AKR stably expressing cancer cells. These results would facilitate the development of novel anticancer drugs targeting for AKR.

Research Products

• [Journal Article] Cloning and characterization of four rabbit aldo-keto reductases featuring broad substrate specificity for xenobiotic and endogenous carbonyl compounds: Their relationship with multiple forms of drug ketone reductases (2014)
  • Author(s): Satoshi Endo, Toshiyuki Matsunaga, Yuki Arai, Kazuo Tajima, Ossama El-Kabbani, Shigeru Yamano, Yasuo Bunai, Akira Hara, Yukio Kitade
  • Journal Title: Drug Metab. Dispos. Volume: 42 Issue: 4 Pages: 803-812
  • DOI: 10.1124/dmd.113.056044
  • Peer Reviewed
• [Journal Article] Synthesis and structure-activity relationship of 2-phenyliminochromene derivatives as inhibitors for AKR1B10 (2013)
  • Author(s): Satoshi Endo, Dawei HU, Miho Suyama, Toshiyuki Matsunaga, Kenji Sugimoto, Yuji Matsuya, Ossama El-Kabbani, Kazuo Kuwata, Akira Hara, Yukio Kitade, Naoki Toyooka
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 21(21) Issue: 21 Pages: 6378-6384
  • DOI: 10.1016/j.bmc.2013.08.059
  • Peer Reviewed
• [Journal Article] Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds (2013)
  • Author(s): Satoshi Endo, Toshiyuki Matsunaga, Atsuko Matsumoto, Yuki Arai, Satoshi Ohno, Ossama El-Kabbani, Kazuo Tajima, Yukio Kitade, Yasuo Bunai, Shigeru Yamano, and Akira Hara
  • Journal Title: Biochem. Pharmacol. Volume: 86 Issue: 9 Pages: 1366-1375
  • DOI: 10.1016/j.bcp.2013.08.024
  • Peer Reviewed
• [Journal Article] Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein (AKR1B19) by oxidized glutathione and SH-reagents (2013)
  • Author(s): Satoshi Endo
  • Journal Title: Chemico-Biological Interactions Volume: 202 Issue: 1-3 Pages: 146-152
  • DOI: 10.1016/j.cbi.2012.11.026
  • Peer Reviewed
• [Journal Article] Characterization of a rabbit morphine 6-dehydrogenase and its two isoforms which function as NAD+-dependent 3α(17β)- hydroxysteroid dehydrogenases (2012)
  • Author(s): Satoshi Endo, Toshiyuki Matsunaga, Airi Fujimoto, Sho Kumada, Yuki Arai, Yoko Miura, Hiroshige Mikamo, Ossama El-Kabbani, Shigeru Yamano, Munekazu Iinuma, Akira Hara
  • Journal Title: Arch. Biochem. Biophys Volume: Vol.529、No.2 Issue: 2 Pages: 131-139
  • DOI: 10.1016/j.abb.2012.11.013
  • Peer Reviewed
• [Journal Article] Inhibition of Human Aldose Reductase-like Protein (AKR1B10) byα- andγ-Mangostins, Major Components of Pericarps of Mangosteen、Biol (2012)
  • Author(s): Midori Soda, Satoshi Endo, Toshiyuki Matsunaga, Hai-Tao Zhao, Ossama El-Kabbani, Munekazu Iinuma, Keiko Yamamura, and Akira Hara
  • Journal Title: Pharm. Bull. Volume: Vol.35、No.11 Pages: 2075-2080
  • Peer Reviewed
• [Journal Article] Inhibition of Human Aldose Reductase-like Protein (AKR1B10) by α- and γ-Mangostins, Major Components of Pericarps of Mangosteen (2012)
  • Author(s): Midori Soda, Satoshi Endo, Toshiyuki Matsunaga, Hai-Tao Zhao, Ossama El-Kabbani, Munekazu Iinuma, Keiko Yamamura, and Akira Hara
  • Journal Title: Biol. Pharm. Bull. Volume: 35 Pages: 2075-2080
  • NAID: 130001872266
  • Peer Reviewed
• [Presentation] 2-Phenyliminochromene誘導体の癌マーカーAKR1B10阻害活性に関する構造活性相関 (2013)
  • Author(s): 陶山美穂、遠藤智史、松永俊之、胡大イ、杉本健士、松谷裕二、豊岡尚樹、桑田一夫、原明
  • Organizer: 第41回構造活性相関シンポジウム
  • Place of Presentation: 兵庫
  • Year and Date: 2013-11-07
• [Presentation] ウサギの3-hydroxyhexobarbital dehydrogenaseはketosteroids、prostaglandin D2、その他のカルボニル化合物に広い特異性を示す還元酵素である (2013)
  • Author(s): 原明、遠藤智史、山野茂、松本淳子、荒井裕貴、松永俊之
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2013-09-13
• [Presentation] 2-Phenyliminochromene誘導体の癌マーカーAKR1B10阻害活性に関する構造活性相関 (2013)
  • Author(s): 陶山 美穂、遠藤 智史、松永 俊之、胡 大イ、杉本 健士、松谷 裕二、豊岡 尚樹、桑田 一夫、原 明
  • Organizer: 第41回構造活性相関シンポジウム
  • Place of Presentation: 西宮
• [Presentation] Ossama El-Kabbani, and Akira Hara、Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein by oxidized glutathione and SH-reagents (2012)
  • Author(s): Satoshi Endo, Sho Kumada, Airi Fujimoto, Toshiyuki Matsunaga, Satoshi Ohno, Jun'ichi Mano, Kazuo Tajima
  • Organizer: ENZYMOLOGY AND MOLECULAR BIOLOGY OF CARBONYL METABOLISM SIXTEENTH INTERNATIONAL MEETING
  • Place of Presentation: Plön, GERMANY
• [Presentation] Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein by oxidized glutathione and SH-reagents (2012)
  • Author(s): Satoshi Endo, Sho Kumada, Airi Fujimoto, Toshiyuki Matsunaga, Satoshi Ohno, Jun'ichi Mano, Kazuo Tajima, Ossama El-Kabbani, and Akira Hara
  • Organizer: ENZYMOLOGY AND MOLECULAR BIOLOGY OF CARBONYL METABOLISM SIXTEENTH INTERNATIONAL MEETING
  • Place of Presentation: Plon, GERMANY
• [Remarks]
  • URL: http://www.gifu-pu.ac.jp/lab/seika/index.html
• [Patent(Industrial Property Rights)] AKR1C3阻害剤 (2013)
  • Inventor(s): 遠藤 智史、松永 俊之、豊岡 尚樹
  • Industrial Property Rights Holder: 岐阜市
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-149089
  • Filing Date: 2013-07-18
• [Patent(Industrial Property Rights)] AKR1C3阻害剤 (2013)
  • Inventor(s): 遠藤智史、松永俊之、豊岡尚樹
  • Industrial Property Rights Holder: 岐阜市
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-149089
  • Filing Date: 2013-07-18