Discovery of drug candidates by using in situ click chemistry

• Project/Area Number: 24689007
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SUZUKI Takayoshi 京都府立医科大学, 医学(系)研究科(研究院), 教授 (90372838)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥26,520,000 (Direct Cost: ¥20,400,000、Indirect Cost: ¥6,120,000); Fiscal Year 2014: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000); Fiscal Year 2013: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000); Fiscal Year 2012: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: ヒストン脱アセチル化酵素 / アイソフォーム / クリックケミストリー / アジド / アルキン / トリアゾール / 阻害薬 / リシン脱アセチル化酵素 / アイソザイム

Outline of Final Research Achievements

In drug discovery, high-throughput screening, structure-based drug design, and ligand-based drug design are generally used. However, these methods take great time and effort.
With the background like this, we tried to identify selective inhibitors using click chemistry. As a result, we rapidly identified promising inhibitors by this method, suggesting the usefulness of this method in drug discovery.

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] Target-guided Synthesis: Medicinal Chemistry Strategy to Allow Target Enzymes Themselves to Synthesize their Own Inhibitors (2014)
  • Author(s): Yukihiro Itoh, Naoki Miyata, Takayoshi Suzuki
  • Journal Title: J. Syn. Org. Chem. Jpn. Volume: 72 Pages: 702-716
  • NAID: 130004548618
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Presentation] 創薬を目指したエピジェネティクス制御化合物の創製 (2015)
  • Author(s): 鈴木孝禎
  • Organizer: 天然物ケミカルバイオロジー地区シンポジウム
  • Place of Presentation: 東北大学
  • Year and Date: 2015-01-15
  • Invited
• [Presentation] エピジェネティクスのケミカルコントロール (2014)
  • Author(s): 鈴木孝禎
  • Organizer: 第18回スクリプス・バイオメディカルフォーラム
  • Place of Presentation: 大阪
  • Year and Date: 2014-11-22
  • Invited
• [Presentation] エピジェネティクス制御化合物の開発 (2014)
  • Author(s): 鈴木孝禎
  • Organizer: 第87回 日本生化学会大会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2014-10-15
• [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, 他
  • Organizer: 日本薬学会 第133年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2013-03-29
• [Presentation] Identification of HDAC3-Selective Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly (2013)
  • Author(s): Yosuke Ota, Takayoshi Suzuki et al
  • Organizer: 2nd Annual Conference ICBS2013
  • Place of Presentation: 京都大学（京都市）
• [Remarks] 京都府立医科大学医薬品化学研究室HP
  • URL: http://www.kpu-m.ac.jp/y/chemistry/publications.html
• [Remarks]
  • URL: http://www.kpu-m.ac.jp/y/chemistry/publications.html