多因子疾患全身性強皮症治療薬のリード創製と最適化

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17H03999
• Research Institution: Kumamoto University
• Principal Investigator: 大塚 雅巳 熊本大学, 大学院生命科学研究部(薬), 客員教授 (40126008)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 全身性強皮症

Outline of Annual Research Achievements

全身性強皮症は皮膚や組織にコラーゲンが蓄積して硬化、線維化する自己免疫疾患である。明確な原因が不明で、根治薬がなく、難病に指定されている。全身性強皮症はTGF-β/Smad系、PI3K/Akt系、自己免疫系などの諸因子が複合的に関与する疾患で、１つの蛋白質を標的として特異的に抑えても他の経路をバイパスとして病態が進行するため、単一標的アプローチでは治癒が困難である。全身性強皮症を治癒させるにはマルチ標的アプローチが必要と考えられる。令和元年度は、細胞の形態変化を指標としたフェノタイプスクリーニングにより研究代表者の合成した化合物のなかから見出された化合物HPH-15、および多彩な生理活性をもつIP6のプロドラッグ体について検討を行った。
平成30年度にHPH-15の10種類の誘導体を合成したが、令和元年度にはその部分構造を一部改変した化合物をさらに10種類合成した。ヒト皮膚細胞をTGF-βで刺激したときのコラーゲン産生に対する抑制効果を調べたところ、令和元年度に合成した10化合物の方が、平成30年度の化合物より強い活性を示す傾向がみられた。
本研究では化合物HPH-15の活性の改善のための構造最適化、HPH-15が作用する標的タンパク質について検討を行った。また、多彩な生理活性をもつIP6のプロドラッグ体についても検討を行った。
平成30年度、令和元年度にはHPH-15の標的蛋白質の探索、およびIP6プロドラッグ体が作用する蛋白質の検討を行った。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] HSP70 induction by bleomycin metal core analogs (2020)
  • Author(s): Taha F.S. Ali, Naomi Taira, Kana Iwamaru, Ryoko Koga, Masahiro Kamo, Mohamed O. Radwan, Hiroshi Tateishi, Hiromasa Kurosaki, Mohamed Abdel-Aziz, Gamal El-Din A.A. Abuo-Rahma, Eman A.M. Beshr, Masami Otsuka, Mikako Fujita
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 30 Pages: 127002
  • DOI: 10.1016/j.bmcl.2020.127002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structure analysis of TIFA involved in innate immunity: Insight into TIFA-dependent signal transduction (2020)
  • Author(s): Teruya Nakamura, Chie Hashikawa, Yuya Yokote, Mami Chirifu, Yoshinari Okamoto, Yuu Taguchi, Jin Gohda, Taishin Akiyama, Kentaro Semba, Shinji Ikemizu, Masami Otsuka, Jun-ichiro Inoue, Yuriko Yamagata
  • Journal Title: Scientific Reports Volume: 10 Pages: 5152
  • DOI: 10.1038/s41598-020-61972-6
  • Peer Reviewed
• [Journal Article] Interruption of Vif/elongin C interaction: In silico and experimental elucidation of the underlying molecular mechanism of benzimidazole-based APOBEC3G stabilizers (2020)
  • Author(s): Mohamed O. Radwan; Daisuke Takaya; Ryoko Koga; Kana Iwamaru; Hiroshi Tateishi; Taha F.S. Ali; Akifumi Takaori-Kondo; Masami Otsuka; Teruki Honma; Mikako Fujita
  • Journal Title: Bioorg. Med. Chem. Volume: 28 Pages: 115409
  • DOI: 10.1016/j.bmc.2020.115409
  • Peer Reviewed
• [Journal Article] New SIRT2 inhibitors: histidine-based bleomycin spin-off (2019)
  • Author(s): Taha F. S. Ali, Halil I. Ciftci, Mohamed O. Radwan, Ryoko Koga, Takeo Ohsugi, Yoshio Okiyama, Teruki Honma, Akiko Nakata, Akihiro Ito, Minoru Yoshida, Mikako Fujita, Masami Otsuka
  • Journal Title: Bioorg, Med. Chem. Volume: 27 Pages: 1767 - 1775
  • DOI: 10.1016/j.bmc.2019.03.003
  • Peer Reviewed
• [Journal Article] Serial Femtosecond X-Ray Diffraction of HIV-1 Gag MA-IP6 Microcrystals at Ambient Temperature (2019)
  • Author(s): Halil I Ciftci, Raymond G Sierra, Chun Hong Yoon, Zhen Su, Hiroshi Tateishi, Ryoko Koga, Koiwai Kotaro, Fumiaki Yumoto, Toshiya Senda, Mengling Liang, Soichi Wakatsuki, Masami Otsuka, Mikako Fujita, Hasan DeMirci
  • Journal Title: Int. J. Mol. Sci. Volume: 20 Pages: 1675
  • DOI: 10.3390/ijms20071675
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Minimum structural requirements for inhibitors of the zinc finger protein TRAF6 (2019)
  • Author(s): Mohamed O. Radwan, Ryoko Koga, Tomohiro Hida, Tomohiko Ejima, Yosuke Kanemaru, Hiroshi Tateishi, Yoshinari Okamoto, Jun-ichiro Inoue, Mikako Fujita, Masami Otsuka
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 29 Pages: 2162 - 2167
  • DOI: 10.1016/j.bmcl.2019.06.050
  • Peer Reviewed
• [Journal Article] Novel p97/VCP inhibitor induces ER stress and apoptosis in both bortezomib sensitive and resistant multiple myeloma cells (2019)
  • Author(s): Nao Nishimura, Mohamed Radwan, Masayuki Amano, Eri Fujii, Hironori Hayashi, Shinya Endo, Shikiko Ueno, Niina Ueno, Hiro Tatetsu, Hiroyuki Hata, Yoshinari Okamoto, Masami Otsuka, Hiroaki Mitsuya, Masao Matsuoka, Yutaka Okuno
  • Journal Title: Cancer Science Volume: 110 Pages: 3275 - 3287
  • DOI: 10.1111/cas.14154
  • Peer Reviewed
• [Journal Article] Antiproliferative-S-Trityl-L-Cysteine Derived Compounds as SIRT2 Inhibitors: Repurposing and Solubility Enhancement (2019)
  • Author(s): Mohamed O. Radwan, Halil I. Ciftci, Taha F. S. Ali, Doha E. Ellakwa, Ryoko Koga, Hiroshi Tateishi, Akiko Nakata, Akihiro Ito, Minoru Yoshida, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Journal Title: Molecules Volume: 24 Pages: 3295
  • DOI: 10.3390/molecules24183295
  • Peer Reviewed
• [Journal Article] Anticancer Activity of Twig Components of Caucasian Beech in Turkey (2019)
  • Author(s): Wataru Shida, Hiroshi Tateishi, Mikako Fujita, Doaa Husham Al-Saadi, Masato Watanabe, Ryoko Koga, Mohamed O. Radwan, Halil I. Ciftci, Sevgi Gezici, Masami Otsuka, Koji Sugimura, Mikiyo Wada, Nazim Sekeroglu, Takashi Watanabe
  • Journal Title: Molecules Volume: 24 Pages: 3850
  • DOI: 10.3390/molecules24213850
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design, synthesis, and biological activity of Plastoquinone analogs as a new class of anticancer agents (2019)
  • Author(s): Nilufer Bayrak, Hatice Yildirim, Mahmut Yildiz, Mohamed O. Radwan, Masami Otsuka, Mikako Fujita, Amac Fatih Tuyun, Halil I. Ciftci
  • Journal Title: Bioorganic Chemistry Volume: 92 Pages: 103255
  • DOI: 10.1016/j.bioorg.2019.103255
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity (2019)
  • Author(s): Halil I. Ciftci, Mohamed O. Radwan, Safiye E. Ozturk, N. Gokce Ulusoy, Ece Sozer, Doha E. Ellakawa, Zeynep Ocak, Mustafa Can, Taha F.S. Ali, Howaida I. Abdalla, Nurettin Yayli, Masami Otsuka, Mikako Fujita
  • Journal Title: Molecules Volume: 24 Pages: 3535
  • DOI: 10.3390/molecules24193535
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-cancer activity of the cell membrane-permeable phytic acid prodrug (2019)
  • Author(s): Takuya Masunaga, Naoki Murao, Hiroshi Tateishi, Ryoko Koga, Takeo Ohsugi, Masami Otsuka, Mikako Fujita
  • Journal Title: Bioorganic Chemistry Volume: 92 Pages: 103240
  • DOI: 10.1016/j.bioorg.2019.103240
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Biological Activity of Plastoquinone Analogs as a New Class of Anticancer Agents (2019)
  • Author(s): Nilufer Bayrak, Hatice Yildirim, Mahmut Yildiz, Mohamed Radwan, Masami Otsuka, Mikako Fujita, Amac Fatih Tuyun, Halilibrahim Ciftci
  • Journal Title: Bioorganic Chemistry Volume: 92 Pages: 103255
  • DOI: 10.1016/j.bioorg.2019.103255
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design, synthesis and biological evaluation of a new series of thiazolyl-pyrazolines as dual EGFR and HER2 inhibitors (2019)
  • Author(s): Sever, B., Altintop, M.D., Radwan, M.O., Ozdemir A., Otsuka, M., Fujita, M., and Ciftci, H.I.
  • Journal Title: European Journal of Medicinal Chemistry Volume: 182 Pages: 111648
  • DOI: 10.1016/j.ejmech.2019.111648
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Novel Series of Chlorinated Plastquinone Analogs: Design, Synthesis, and Evaluation of Anticancer Activity (2019)
  • Author(s): Nilufer Bayrak, Hatice Yildirim, Mahmut Yildiz, Mohamed O. Radwan, Masami Otsuka, Mikako Fujita, Halil I. Ciftci, Amac Fatih Tuyun
  • Journal Title: Chemical Biology & Drug Design Volume: 0 Pages: 1-12
  • DOI: 10.1111/cbdd.13651
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Strategic Design of Drug Core Structure (2019)
  • Author(s): Masami Otsuka
  • Organizer: Ege University-Kumamoto University-Karadeniz Technical University Collaborative Meeting at Multidisciplinary studies
  • Int'l Joint Research / Invited
• [Presentation] HIV-2 Vpx/Vpr regulates their stability using two motifs (2019)
  • Author(s): Kazunori Shimagaki, Ryoko Koga, Haruna Fujino, Halil Ibrahim Ciftci, Minami Yamamoto, Hiroshi Tateishi, Masami Otsuka, Yoshihiro Yamaguchi, Mikako Fujita
  • Organizer: The fifth International Mediterranean Symposium on Medicinal and Aromatic Plants
  • Int'l Joint Research
• [Presentation] Strategic Design of Drug Core Structure: A Bleomycin Spinout Story (2019)
  • Author(s): Masami Otsuka
  • Organizer: The fifth International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research / Invited
• [Presentation] Pentacyclic triterpene derivatives with selective anti-proliferative effect against chronic myelogenous leukemia (2019)
  • Author(s): Mohamed O. Radwan, Halil Ciftci, Safiye Emirdag-Ozturk, N. Gokce Ulsoy, Ece Sozer, Nurettin Yayli, Mikeko Fujita, Masami Otsuka
  • Organizer: The fifth International Symposium on Pharmaceutical and Biomedical Sciences
  • Int'l Joint Research
• [Presentation] 亜鉛結合性低分子化合物によるTRAF6からのシグナル阻害 (2019)
  • Author(s): 下園理恵、古賀涼子、ラドワン モハメド オスマン、立石大、江島智彦、金丸陽亮、井上純一郎、大塚雅巳、藤田美歌子
  • Organizer: 日本ケミカルバイオロジー学会第14回年会
• [Presentation] 人工イノシトールリン脂質誘導体を用いた新規HIV-1根絶法の開発 (2019)
  • Author(s): 立石大、門出和精、安楽健作、古賀涼子、チッフチハリルイブラヒム、小祝孝太郎、湯本史明、千田俊哉、大塚雅巳、藤田美歌子
  • Organizer: 日本ケミカルバイオロジー学会第14回年会
• [Presentation] カルジオリピンとHIV-1 Gag MAドメインとの結合解析と創薬への展開 (2019)
  • Author(s): 坂本亜里紗、立石大、門出和精、古賀涼子、小祝孝太郎、湯本史明、田辺幹雄、千田俊哉、三隅将吾、大塚雅巳、藤田美歌子、安楽健作
  • Organizer: 第37回メディシナルケミストリーシンポジウム
• [Remarks]
  • URL: http://www.pharm.kumamoto-u.ac.jp/Labs/bunsigouseiHP/index.html