Discovery of a novel naftopidil-based therapeutic agent for malignant mesothelioma and mechanism of action

• Project/Area Number: 16K07186
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Hyogo Medical University (2022); Hyogo University of Health Sciences (2016-2021)
• Principal Investigator: Tadashi Shimizu 兵庫医科大学, 薬学部, 教授 (40509022)
• Co-Investigator(Kenkyū-buntansha): 長屋 寿雄 兵庫医科大学, 医学部, 助教 (60464343) ; 大野 喜也 兵庫医科大学, 薬学部, 講師 (40509155)
• Project Period (FY): 2016-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: ナフトピジル / 中皮腫 / 探索合成 / 代謝物 / 膀胱がん / 薬物動態 / in vio評価 / 悪性中皮腫 / 溶解性 / 塩酸塩 / アフィニティ樹脂 / 膀胱癌 / ドラッグリポジショニング / 光学分割 / 抗がん活性 / ターゲット探索

Outline of Final Research Achievements

In this study, we developed research on the discovery and synthesis of new derivatives with anticancer activity based on naftopidil or new anticancer activity of its metabolites, but were unable to create a derivative with significant anticancer activity against malignant mesothelioma. However, in the course of our research, we found that HUHS190, one of the metabolites of naftopidil, has an effective action against bladder cancer at the cellular level, and established a route for mass synthesis for use in in vivo experiments. In addition, we investigated the pharmacokinetic profile of HUHS190 and its efficacy in a mouse in vivo model of bladder cancer.

Academic Significance and Societal Importance of the Research Achievements

本研究では、当初に目的としていた中皮腫の治療薬創製はできなかったが、ナフトピジル代謝物が膀胱がんに有効であることを薬物動態および薬理学的な動物モデルで示すことができた。ナフトピジル代謝物は臨床での安全性が明らかとなっている化合物であることから、本化合物をドラッグリポジショニングすることにより、新たな膀胱がん治療薬として開発できる可能性がある。さらに、本研究により医薬品代謝物に焦点を当てた新規治療薬を創製できる研究展開を示すことが出来たと考えられる。

Research Products

• [Journal Article] Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug (2020)
  • Author(s): T. Shimizu, K. Yamaguchi, M Yamamoto, R. Kurioka, Y. Kino, W. Matsunaga, S. Nakao, H.Fukuhara, A. Tanaka, A. Gotoh, M. Mabuchi
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 30 Pages: 126744-126744
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Water-Soluble Indolylmaleimide Derivative IM-93 Showing Dual Inhibition of Ferroptosis and NETosis. (2019)
  • Author(s): K. Dodo, E*. Kuboki*, T Shimizu* (*equally contributed first author), R. Imamura, M. Magarisawa, M. Takahashi, T. Tokuhiro, S. Yasumoto, K. Asano, S. Nakao, N. Terayama, T.Suda, M. Tanaka, M. Sodeoka.
  • Journal Title: ACS Med Chem Lett. Volume: 10 Issue: 9 Pages: 1272-1278
  • DOI: 10.1021/acsmedchemlett.9b00142
  • Peer Reviewed / Open Access
• [Journal Article] Novel Metabolically Stable PCA-1/ALKBH3 Inhibitor Has Potent Antiproliferative Effects on DU145 Cells In Vivo. (2018)
  • Author(s): Ueda M, Shimizu T, Mabuchi M, Horiike K, Kitae K, Hase H, Ueda Y, Tsujikawa K, Tanaka A
  • Journal Title: Anticancer Res. Volume: 38 Issue: 1 Pages: 211-218
  • DOI: 10.21873/anticanres.12210
  • Peer Reviewed
• [Journal Article] Indolylmaleimide Derivative IM-17 Shows Cardioprotective Effects in Ischemia-Reperfusion Injury. (2018)
  • Author(s): Dodo K, Shimizu T, Sasamori J, Aihara K, Terayama N, Nakao S, Iuchi K, Takahashi M, Sodeoka M.
  • Journal Title: ACS Med Chem Lett. Volume: 9 Issue: 3 Pages: 182-187
  • DOI: 10.1021/acsmedchemlett.7b00454
  • Peer Reviewed / Open Access
• [Journal Article] Systematic Trial for Evaluating Docetaxel in a Human Prostate Cancer Cell DU145 Xenograft Model (2017)
  • Author(s): MIYUKI MABUCHI, MASAHIRO UEDA, YURI YOSHIDA, KOTA HORIIKE, KENTA YAMAOKA, SYUHEI NAKAO, TADASHI SHIMIZU, YUKO UEDA, KAZUTAKE TSUJIKAWA, AKITO TANAKA
  • Journal Title: anticancer research Volume: 37 Issue: 4 Pages: 1665-1676
  • DOI: 10.21873/anticanres.11496
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor. (2017)
  • Author(s): Nakao S, Mabuchi M, Wang S, Kogure Y, Shimizu T, Noguchi K, Tanaka A, Dai Y.
  • Journal Title: Bioorg Med Chem Lett. Volume: 27 Issue: 14 Pages: 3167-3172
  • DOI: 10.1016/j.bmcl.2017.05.025
  • Peer Reviewed
• [Journal Article] The phosphatidylethanolamine derivative diDCP-LA-PE mimics intracellular insulin signaling. (2016)
  • Author(s): T. Nishizaki, A. Gotoh, T.Shimizu, A. Tanaka
  • Journal Title: Sci.Rep. Volume: 6 Issue: 1
  • DOI: 10.1038/srep27267
  • Peer Reviewed / Open Access
• [Journal Article] Structure–Activity Relationship Study of 3-Amino-2-indolyllactam Derivatives: Development of Inhibitors of Oxidative Stress-Induced Necrosis (2016)
  • Author(s): Kosuke Dodo, Kenji Hayamizu, Tadashi Shimizu, Mikko Sodeoka
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 886-898
  • DOI: 10.1248/cpb.c16-00259
  • NAID: 130005160020
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 「臨床応用」を志向した創薬研究～大学発の創薬を目指して～ (2016)
  • Author(s): 清水 忠
  • Organizer: 第2回近畿薬学シンポジウム・化学系の若い力
  • Place of Presentation: 大阪大学薬学研究科1号館4階沢井ホール（大阪府吹田市）
  • Year and Date: 2016-06-04
  • Invited