Development of anticancer agents for zinc-proteins related to cancer

• Project/Area Number: 26460148
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kumamoto University
• Principal Investigator: OKAMOTO Yoshinari 熊本大学, 大学院生命科学研究部(薬), 助教 (20194409)
• Co-Investigator(Renkei-kenkyūsha): OTSUKA Masami 熊本大学, 大学院生命科学研究部, 教授 (40126008)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 癌 / 浸潤・転移 / ADAM17 / Rasタンパク / 亜鉛配位子

Outline of Final Research Achievements

It is well known that various proteins are relating to cancer. Among them, I focused on a disintegrin and metalloprotease 17 (ADAM17) and farnesyltransferase (FTase).
We are successful to synthesis of a new pyridine /cysteamine based zinc chelator equipped with butynyloxybenzenesulfonyl group (as a ADAM17 inhibitor) or farnesyl group (as a FTase inhibitor) for recognition of these proteins.
IC50 value of ADAM17 inhibitor against the THP-1 cell was 3.22μM, and IC50 value of FTase inhibitor against the dansyl-GCLVS was 0.90μM.

Research Products

• [Journal Article] Synthesis of the biotinylated anti-HIV compound BMMP and the target identification study. (2016)
  • Author(s): Kamo M, Tateishi H, Koga R, Okamoto Y, Otsuka M, Fujita M.
  • Journal Title: Bioorg. Med. Chem. Volume: 26 Issue: 1 Pages: 43-45
  • DOI: 10.1016/j.bmcl.2015.11.036
  • Peer Reviewed
• [Journal Article] Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (2016)
  • Author(s): Radwan, Mohamed O.; Sonoda, Sachiko; Ejima, Tomohiko; Tanaka, Ayumi; Koga, Ryoko; Okamoto, Yoshinari; Fujita, Mikako; Otsuka, Masami
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 18 Pages: 4398-4405
  • DOI: 10.1016/j.bmc.2016.07.030
  • Peer Reviewed
• [Journal Article] Novel metal chelating molecules with anticancer activity. Striking effect of the imidazole substitution of the histidine-pyridine-histidine system (2015)
  • Author(s): Ali, Taha F. S.; Iwamaru, Kana; Ciftci, Halil Ibrahim; Koga, Ryoko; Matsumoto, Masahiro; Oba, Yasunori; Kurosaki, Hiromasa; Fujita, Mikako; Okamoto, Yoshinari; Otsuka, Masami et. al.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 23 Issue: 17 Pages: 5476-5482
  • DOI: 10.1016/j.bmc.2015.07.044
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] L-Histidyl-glycyl-glycyl-L-histidine. Amino-acid structuring of the bleomycin-type pentadentate metal-binding environment capable of efficient double-strand cleavage of plasmid DNA (2015)
  • Author(s): Ida, Satomi; Iwamaru, Kana; Fujita, Mikako; Okamoto, Yoshinari; Kudo, Yuri; Kurosaki, Hiromasa; Otsuka, Masami
  • Journal Title: Bioorganic Chemistry Volume: 62 Pages: 8-14
  • DOI: 10.1016/j.bioorg.2015.06.007
  • Peer Reviewed
• [Journal Article] Design and synthesis of lipid-coupled inositol 1, 2, 3, 4, 5, 6-hexakisphosphate derivatives exhibiting high-affinity binding for HIV-1 MA domain (2014)
  • Author(s): Hiroshi Tateishi, Kensaku Anraku, Ryoko Koga, Yoshinari Okamoto, Mikako Fujita, Masami Otsuka
  • Journal Title: Organic & Biomolecular Chemistry Volume: (First published online) Issue: 27 Pages: 5006-5022
  • DOI: 10.1039/c4ob00350k
  • Peer Reviewed
• [Presentation] 抗HIV剤BMMPの作用機序解明 (2017)
  • Author(s): 加茂真宏，立石大，山本充奈美，岡本良成，森川裕子，三隅将吾，大塚雅巳，藤田美歌子
  • Organizer: 日本薬学会第１３７年会
  • Place of Presentation: 東北大学
  • Year and Date: 2017-03-24
• [Presentation] DHMEQを基盤とした新しい生物活性物質の設計と合成，及び機能解析 (2016)
  • Author(s): 本邑健太，岡本良成，古賀涼子，馬塲菜々美，藤田美歌子，梅澤一夫，大塚雅巳
  • Organizer: 第３３回日本薬学会九州支部大会
  • Place of Presentation: 鹿児島大学
  • Year and Date: 2016-12-03
• [Presentation] Development of Inhibitors for Zinc Proteins Related to Cancer (2016)
  • Author(s): Yoshinari Okamoto, Yasunori Oba, Ayumi Tanaka, Mika Kawabuchi, Hiroshi Tateishi, Mikako Fujita, Masami Otsuka
  • Organizer: Japan-Turkey International Symposium on Pharmaceutical and Biomedical Sciences
  • Place of Presentation: Kumamoto University
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] Zinc-mediated binding of a low-molecular-weight stabilizer of the host anti-viral factor APOBEC3G (2016)
  • Author(s): Radwan, Mohamed O.; Sonoda, Sachiko; Ejima, Tomohiko; Tanaka, Ayumi; Koga, Ryoko; Okamoto, Yoshinari; Fujita, Mikako; Otsuka, Masami
  • Organizer: 252nd American Chemical Society National Meeting & Exposition
  • Place of Presentation: Pennsylvania Convention Center
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Design and synthesis of small molecule Hsp70 inducers (2016)
  • Author(s): Ali, Taha; Taira, Naomi; Koga, Ryoko; Okamoto, Yoshinari; Otsuka, Masami; Fujita, Mikako
  • Organizer: 252nd American Chemical Society National Meeting & Exposition
  • Place of Presentation: Pennsylvania Convention Center
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Synthesis and applications of biotinylated zinc binding SN1 (2016)
  • Author(s): Mohamed RADWAN, Ryoko KOGA, Yoshinari OKAMOTO, Mikako FUJITA, Masami OTSUKA
  • Organizer: 日本薬学会第１３６年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] 抗 HIV 剤 BMMP の作用機序解明と活性改良 (2016)
  • Author(s): 加茂 真宏, 立石 大, 山本 充奈美, 岡本 良成, 森川 裕子, 大塚 雅巳, 藤田美歌子
  • Organizer: 日本薬学会第１３６年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-03-26
• [Presentation] 抗 HIV 剤 BMMP の作用機序解明及び活性改良 (2015)
  • Author(s): Masahiro Kamo, Hiroshi Tateishi, Minami Yamamoto, Yoshinari Okamoto, Yuko Morikawa, Shogo Misumi, Masami Otsuka, Mikako Fujita
  • Organizer: 第６３回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2015-11-22
• [Presentation] 抗HIV剤BMMPの作用機序解明と構造改変の試み (2015)
  • Author(s): 加茂真宏，立石大，山本充奈美，岡本良成，森川裕子，三隅将吾，大塚雅巳，藤田美歌子
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学・兵庫医療大学
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] 新規HIV-1放出抑制剤を目指したイノシトールリン脂質誘導体の創製 (2015)
  • Author(s): 立石大，安楽健作，村尾直樹，門出和精，原田信志，古賀涼子，岡本良成，藤田美歌子，大塚雅巳
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学・兵庫医療大学
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] Novel metal chelating molecules with anticancer activity (2015)
  • Author(s): Taha ALI，岩丸佳奈，Halil CIFTCI，古賀涼子，黒崎博雅，藤田美歌子，岡本良成，秀拓一郎，牧野敬史，倉津純一，中尾光善，梅澤一夫，Mohamed ABDEL-AZIZ，Gamal El-Din ABUO-RAHMA，Eman BESHR，大塚雅巳
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学・兵庫医療大学
  • Year and Date: 2015-03-26 – 2015-03-28
• [Presentation] A novel zinc chelating inhibotor of NF-kB activation : Biotin modification and docking study (2014)
  • Author(s): モハメド オスマン ラドワン，古賀涼子，岡本良成，藤田美歌子，大塚雅巳
  • Organizer: 第31回日本薬学会九州支部大会
  • Place of Presentation: 第一薬科大学
  • Year and Date: 2014-12-06 – 2014-12-07
• [Presentation] Gagに作用する抗HIV剤BMMPの作用機序解明と活性改良の試み (2014)
  • Author(s): 加茂真宏，立石大，岡本良成，森川裕子，大塚雅巳，藤田美歌子
  • Organizer: 第28回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-12-03 – 2014-12-05
• [Presentation] HIV-1MAタンパク質とホスファチジルイノシトール4,5-2リン酸との結合部位を標的とした抗HIV薬の設計と合成 (2014)
  • Author(s): 安楽健作，立石大，古賀涼子，岡本良成，藤田美歌子，大塚雅巳
  • Organizer: 第３２回メディシナルケミストリーシンポジウム
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2014-11-26 – 2014-11-28
• [Presentation] Gagに作用する抗HIV化合物BMMPの作用機序解明と活性改良の検討 (2014)
  • Author(s): 加茂真宏，立石大，岡本良成，森川裕子，大塚雅巳，藤田美歌子
  • Organizer: 第６２回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-10 – 2014-11-12