Synthesis of HDAC inhibitors that locally develop their inhibition activity in cells

• Project/Area Number: 24659050
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Nagoya City University
• Principal Investigator: MIYATA Naoki 名古屋市立大学, 薬学研究科(研究院), 教授 (50114674)
• Co-Investigator(Renkei-kenkyūsha): NAKAGAWA Hidehiko 名古屋市立大学, 大学院薬学研究科, 教授 (80281674)
• Research Collaborator: YAMADA Souta
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ヒストン脱アセチル化酵素 / エピジェネティクス / ケミカルバイオロジー / 細胞内局在性 / 光解除性保護基 / 分子標的治療薬 / 制がん剤 / 蛍光検出 / ｴﾋﾟｼﾞｪﾈﾃｨｸｽ / ケージド化合物 / ヒストン脱アセチル化酵素阻害薬

Outline of Final Research Achievements

To elucidate the association between the localization and the function of histone deacetylases (HDACs) in cells, we designed and synthesized HDAC inhibitors which locally develop their activity in cells. We used a caged technique to control the HDAC activity. The synthesized HDAC inhibitors with photo-labile protecting group time-dependently inhibited HDAC activity under the visible light irradiation conditions. These results showed that these HDAC inhibitors can be controlled their activity by visible light irradiation even in the living cell systems and become a useful tool to elucidate the association between the localization and the function of HDAC in cells.

Research Products

• [Journal Article] Identification of Novel SIRT2-Selective Inhibitors Using a Click Chemistry Approach (2014)
  • Author(s): 109. Prima R. Tatum, Hideyuki Sawada, Yosuke Ota, Yukihiro Itoh, Peng Zhan, Naoya Ieda, Hidehiko Nakagawa, Naoki Miyata, Takayoshi Suzuki.
  • Journal Title: Bioorg. Med. Chem. Lett Volume: 24 Issue: 8 Pages: 1871-1874
  • DOI: 10.1016/j.bmcl.2014.03.026
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Biological Activity of NCC149 Derivatives as Histone Deacetylase 8-Selective Inhibitors. (2014)
  • Author(s): Suzuki T, Muto N, Bando M, Itoh Y, Masaki A, Ri M, Ota Y, Nakagawa H, Iida S, Shirahige K, Miyata N.
  • Journal Title: ChemMedChem. Volume: 9 Issue: 3 Pages: 657-664
  • DOI: 10.1002/cmdc.201300414
  • Peer Reviewed
• [Journal Article] Identification of Highly Selective and Potent Histone Deacetylase 3 Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly (2013)
  • Author(s): 98. Takayoshi Suzuki, Yuki Kasuya, Yukihiro Itoh, Yosuke Ota, Peng Zhan, Kaori Asamitsu, Hidehiko Nakagawa, Takashi Okamoto and Naoki Miyata.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: e68669-e68669
  • DOI: 10.1371/journal.pone.0068669
  • Peer Reviewed
• [Journal Article] Small-molecular modulators of cancer-related epigenetic mechanisms (2013)
  • Author(s): Yukihiro Itoh , Takayoshi Suzuki and Naoki Miyata
  • Journal Title: Mol. Biosyst. Volume: 9 Issue: 5 Pages: 873-896
  • DOI: 10.1039/c3mb25410k
  • Peer Reviewed
• [Journal Article] Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate Libraries (2012)
  • Author(s): Takayoshi Suzuki, Yosuke Ota, Masaki Ri, Masashige Bando, Aogu Gotoh, Yukihiro Itoh, Hiroki Tsumoto, Prima R. Tatum, Tamio Mizukami, Hidehiko Nakagawa, Shinsuke Iida, Ryuzo Ueda, Katsuhiko Shirahige, and Naoki Miyata.
  • Journal Title: J. Med. Chem. Volume: 55 Issue: 22 Pages: 9562-9575
  • DOI: 10.1021/jm300837y
  • Peer Reviewed
• [Journal Article] Design, Synthesis, and Biological Activity of a Novel Series of Human Sirtuin-2-Selective Inhibitors (2012)
  • Author(s): Takayoshi Suzuki, Mohammed Naseer Ahmed Khan, Hideyuki Sawada, Erika Imai, Yukihiro Itoh, Katsura Yamatsuta, Natsuko Tokuda, Jun Takeuchi, Takuya Seko, Hidehiko Nakagawa, and Naoki Miyata
  • Journal Title: J. Med. Chem. Volume: 55 Issue: 12 Pages: 5760-5773
  • DOI: 10.1021/jm3002108
  • Peer Reviewed
• [Journal Article] Loss of deacetylation activity of hdac6 affects emotional behavior in mice (2012)
  • Author(s): Masahide Fukada
  • Journal Title: PLoS One Volume: 7 Issue: 2 Pages: e30924-e30924
  • DOI: 10.1371/journal.pone.0030924
  • Peer Reviewed
• [Presentation] クマリン構造を有する光で活性制御可能な HDAC 阻害剤の開発 (2015)
  • Author(s): 山田創太、家田直弥、川口充康、宮田直樹、中川秀彦
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Development of a caged HDAC inhibitor with 7-diethylaminocoumarin-type photolabile protecting group (2014)
  • Author(s): Sota Yamada, Naoya Ieda, Mitsuyasu Kawaguchi, Naoki Miyata, Hidehiko Nakagawa
  • Organizer: ICBS2014
  • Place of Presentation: San Francisco
  • Year and Date: 2014-11-17 – 2014-11-19
• [Presentation] 7-Diethylaminocoumarin型光解除性保護基を用いたケージドHDAC阻害剤の開発 (2014)
  • Author(s): 山田創太、家田直弥、川口充康、宮田直樹、中川秀彦
  • Organizer: 第67回日本酸化ストレス学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-09-04 – 2014-09-05
• [Presentation] 7-Diethylaminocoumarin型光解除性保護基を導入したケージドHDAC阻害剤の合成と機能評価 (2014)
  • Author(s): 山田創太、家田直弥、川口充康、宮田直樹、中川秀彦
  • Organizer: 日本ケミカルバイオロジー学会第９回年会
  • Place of Presentation: 大阪
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] HDAC8選択的阻害薬の創製研究 (2014)
  • Author(s): 太田庸介、伊藤幸裕、武藤伸輔、中川秀彦、宮田直樹、鈴木孝禎
  • Organizer: 第31回 メディシナルケミストリーシンポジウム
  • Place of Presentation: 広島
  • Invited
• [Presentation] クリックケミストリーを用いたHDAC8選択的阻害薬の創製研究：リード化合物探索から構造最適化研究まで (2013)
  • Author(s): 太田庸介、武藤伸輔、伊藤幸裕、中川秀彦、宮田直樹、鈴木孝禎
  • Organizer: 第６３回日本薬学会近畿支部大会
  • Place of Presentation: 京田辺
  • Invited
• [Presentation] HDAC3選択的阻害薬の創製と化学遺伝学的応用研究 (2013)
  • Author(s): 伊藤幸裕、粕谷侑輝、中川秀彦、水上民夫、宮田直樹、鈴木孝禎
  • Organizer: 日本ケミカルバイオロジー学会 第8回年会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Click chemistryによるHDAC阻害薬ライブラリーの構築とアイソザイム選択的阻害薬の同定 (2013)
  • Author(s): 伊藤幸裕、太田庸介、粕谷侑輝、中川秀彦、宮田直樹、鈴木孝禎
  • Organizer: 第11回次世代を担う有機化学シンポジウム
  • Place of Presentation: 東京
  • Invited
• [Presentation] クリックケミストリーを用いたHDAC阻害薬の探索研究 (2013)
  • Author(s): 後藤仰、鈴木孝禎、伊藤幸裕、粕谷佑輝、太田庸介、中川秀彦、宮田直樹
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 新規SIRT2選択的阻害薬の創製 ～Structure-based Drug DesignによるSIR (2013)
  • Author(s): 澤田英之、鈴木孝禎、今井英里佳、Mohammed Naseer Ahmed KHAN、中川秀彦、宮田直樹
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] 新規SIRT2選択的阻害薬の創製 (2012)
  • Author(s): 澤田英之, 鈴木孝禎, 今井英里佳, Mohammed Naseer Ahmed Khan, 中川秀彦, 宮田直樹
  • Organizer: 日本ケミカルバイオロジー学会 第7回年会
  • Place of Presentation: 京都
• [Presentation] クリックケミストリーを用いたHDAC阻害薬用トリアゾール化合物ライブラリーの構築 (2012)
  • Author(s): 後藤仰, 鈴木孝禎, 粕谷 侑輝, 中川秀彦, 宮田直樹
  • Organizer: 第４２回複素環化学討論会
  • Place of Presentation: 京都
• [Presentation] クリックケミストリーを用いたHDAC3 選択的阻害薬の迅速探索 (2012)
  • Author(s): 後藤仰，鈴木孝禎，粕谷侑輝，中川秀彦2，宮田直樹
  • Organizer: 第３０回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京
• [Presentation] 新規HDAC8選択的阻害薬の開発と生物活性評価
  • Author(s): 3. 太田庸介、伊藤幸裕、武藤伸輔、中川秀彦、宮田直樹、鈴木孝禎
  • Organizer: 日本薬学会 第134年会
  • Place of Presentation: 熊本