Precise Synthetic Modifications of Proteins

• Project/Area Number: 17H01522
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: Kanai Motomu 東京大学, 大学院薬学系研究科(薬学部), 教授 (20243264)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥41,990,000 (Direct Cost: ¥32,300,000、Indirect Cost: ¥9,690,000); Fiscal Year 2019: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000); Fiscal Year 2018: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2017: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
• Keywords: 抗体ー薬物複合体 / トリプトファン / 抗がん剤 / ラジカル / 官能基許容性 / タンパク質修飾 / リン酸化 / ヒストン修飾 / 酸化 / 抗体 / ADC / 電解酸化 / 有機合成化学 / 薬学 / タンパク質 / 生物機能 / 合成化学 / 蛋白質 / 有機化学

Outline of Final Research Achievements

The goal of this project was to synthesize highly homogeneous antibody-drug conjugates (ADC) using the originally developed tryptophan-selective protein modification reaction and evaluate their activities. We synthesized keto-ABNO covalently bound to an anticancer drug. The molecules were conjugated to an antibody to produce ADCs with a controlled drug / antibody ratio. Those tryptophan-ADCs were toxic to cancer cells expressing antigens that bind to the antibody. It was shown that the tryptophan-ADCs can be synthesized with high homogeneity and has high potential as a novel anticancer agent.

Academic Significance and Societal Importance of the Research Achievements

副作用が低く、効果が高い抗がん剤の開発が広く望まれている。強い細胞毒性を持つ分子を抗体に結合させて、毒をがん細胞選択的に送り込む抗体ー薬物複合体は、そのような抗がん剤であると注目されている。従来の合成法では、抗体の様々な位置に不均質の結合数で薬物が結合した抗体ー薬物複合体しか作れなかった。一方で、我々が開発した方法を用いると、特定の位置に数を定めて抗体ー薬物複合体を合成できるようになった。この新しい抗体ー薬物複合体は、抗がん効果を示すことを明らかとした。

Research Products

• [Int'l Joint Research] テキサスA＆M大学(米国)
• [Int'l Joint Research] ボルドー大学(フランス)
• [Int'l Joint Research] IMDEA(スペイン)
• [Journal Article] Nanoscale view of amyloid photodynamic damage (2020)
  • Author(s): P. Bondia, J. Torra, C. M. Tone, T. Sawazaki, A. Valle, B. Sot, S. Nonell, M. Kanai, Y. Sohma, C. Flors
  • Journal Title: J. Am. Chem. Soc. Volume: 142 Issue: 2 Pages: 922-930
  • DOI: 10.1021/jacs.9b10632
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Design and properties of [Met35 (O)] Aβ42-lactam (Asp23/Lys28) possessing a lactam tether as a salt-bridge surrogate (2019)
  • Author(s): Masashi Yamamoto, Kiyomichi Shinoda, Daisuke Sasaki, Motomu Kanai, Youhei Sohma
  • Journal Title: Bioorg. Med. Chem. Volume: 27 Issue: 5 Pages: 888-893
  • DOI: 10.1016/j.bmc.2019.01.038
  • Peer Reviewed
• [Journal Article] Photo-oxygenation inhibits tau amyloid formation (2019)
  • Author(s): Suzuki T*, Hori Y*, Sawazaki T, Shimizu Y, Nemoto Y, Taniguchi A, Ozawa S, Sohma Y, Kanai M, Tomita T
  • Journal Title: Chem. Commun. Volume: 55(44) Issue: 44 Pages: 6165-6168
  • DOI: 10.1039/c9cc01728c
  • Peer Reviewed / Open Access
• [Journal Article] Site-Selective Synthetic Acylation of a Target Protein in Living Cells Promoted by a Chemical Catalyst/Donor System. (2019)
  • Author(s): Hamajima W, Fujimura A, Fujiwara Y, Yamatsugu K, Kawashima SA, Kanai M.
  • Journal Title: ACS Chemical Biology Volume: 14 Issue: 6 Pages: 1102-1109
  • DOI: 10.1021/acschembio.9b00102
  • Peer Reviewed
• [Journal Article] Synthetic Methodology-Driven Chemical Protein Modifications (2019)
  • Author(s): Katsuya Maruyama, Motomu Kanai
  • Journal Title: Chem. Lett. Volume: 48 Issue: 11 Pages: 1421-1432
  • DOI: 10.1246/cl.190652
  • NAID: 130007741760
  • Peer Reviewed / Open Access
• [Journal Article] Photophysical properties and application in live cell imaging of B,B-fluoro-perfluoroalkyl BODIPYs (2019)
  • Author(s): Taniguchi Atsuhiko、Sawazaki Taka、Shimizu Yusuke、Sohma Youhei、Kanai Motomu
  • Journal Title: MedChemComm Volume: 印刷中 Issue: 7 Pages: 1121-1125
  • DOI: 10.1039/c9md00011a
  • Peer Reviewed
• [Journal Article] Convergent and Functional-Group-Tolerant Synthesis of B-Organo BODIPYs (2018)
  • Author(s): Sawazaki Taka、Shimizu Yusuke、Oisaki Kounosuke、Sohma Youhei、Kanai Motomu
  • Journal Title: Organic Letters Volume: 20 Issue: 24 Pages: 7767-7770
  • DOI: 10.1021/acs.orglett.8b03138
  • Peer Reviewed
• [Journal Article] Hydroxy Group Directed Catalytic Hydrosilylation of Amides (2018)
  • Author(s): Ni Jizhi、Oguro Tsubasa、Sawazaki Taka、Sohma Youhei、Kanai Motomu
  • Journal Title: Organic Letters Volume: 20 Issue: 23 Pages: 7371-7374
  • DOI: 10.1021/acs.orglett.8b03014
  • Peer Reviewed
• [Journal Article] Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts (2018)
  • Author(s): Yamatsugu Kenzo、Furuta Masahiro、Xi Siqi、Amamoto Yoshifumi、Liu Jiaan、Kawashima Shigehiro A.、Kanai Motomu
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 19 Pages: 5359-5367
  • DOI: 10.1016/j.bmc.2018.07.009
  • Peer Reviewed
• [Journal Article] Leading approaches in synthetic epigenetics for novel therapeutic strategies (2018)
  • Author(s): Yamatsugu Kenzo、Kawashima Shigehiro A、Kanai Motomu
  • Journal Title: Current Opinion in Chemical Biology Volume: 46 Pages: 10-17
  • DOI: 10.1016/j.cbpa.2018.03.011
  • Peer Reviewed
• [Journal Article] Near-Infrared Photoactivatable Oxygenation Catalysts of Amyloid Peptide (2018)
  • Author(s): Ni Jizhi、Taniguchi Atsuhiko、Ozawa Shuta、Hori Yukiko、Kuninobu Yoichiro、Saito Takashi、Saido Takaomi C.、Tomita Taisuke、Sohma Youhei、Kanai Motomu
  • Journal Title: Chem Volume: 4 Issue: 4 Pages: 807-820
  • DOI: 10.1016/j.chempr.2018.02.008
  • Peer Reviewed
• [Presentation] Chemical catalysis targeting biomacromolecules (2020)
  • Author(s): 金井 求
  • Organizer: Institut de Biologie Physico-Chimique, Paris,
  • Invited
• [Presentation] Chemical catalysis targeting biomacromolecules (2020)
  • Author(s): 金井 求
  • Organizer: Department Chemie, LMU München, Chemical Biology of Epigenetic Modification
  • Invited
• [Presentation] Chemical Catalysis Targeting Biomacromolecules (2019)
  • Author(s): 金井 求
  • Organizer: Chemical Biology Seminar Series, Department of Chemistry, Texas A&M University
  • Invited
• [Presentation] Transition Metal-Free Tryptophan-Selective Bioconjugation of Proteins (2019)
  • Author(s): 金井 求
  • Organizer: Symposium “Covalent Inhibition beyond Cysteine” the 257th ACS National meeting & exposition, Orlando, FL
  • Int'l Joint Research / Invited
• [Presentation] 生体分子の構造変換ダイナミズムへの人工介入を目指した触媒研究 (2019)
  • Author(s): 金井 求
  • Organizer: サントリー生命科学財団
  • Invited
• [Presentation] Oxidative Functionalization of Proteins (2019)
  • Author(s): 金井 求
  • Organizer: The 47th Naito Conference on C-H Bond Activation and Transformation, 札幌
  • Int'l Joint Research / Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2019)
  • Author(s): 金井 求
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress (ISHC), Kyoto
  • Int'l Joint Research / Invited
• [Presentation] 生体分子機能の制御と拡張を目指す化学触媒研究 (2019)
  • Author(s): 金井 求
  • Organizer: 名古屋大学工学研究科
  • Invited
• [Presentation] 生体分子構造変換ダイナミズムへの化学介入 (2019)
  • Author(s): 金井 求
  • Organizer: 第１２回CHEMBIOハイブリッドレクチャー、東京大学本郷キャンパス 武田先端知ビル 武田ホール
  • Invited
• [Presentation] 生体分子構造変換ダイナミズムへの化学介入 (2019)
  • Author(s): 金井 求
  • Organizer: 田辺三菱製薬 横浜事業所
  • Invited
• [Presentation] 反応開発を基軸とするタンパク質化学修飾 (2019)
  • Author(s): 金井 求
  • Organizer: 日本プロセス化学会2019 ウインターシンポジウム、京都
  • Invited
• [Presentation] Chemical Catalysis Targeting Biomacromolecules (2019)
  • Author(s): Motomu Kanai
  • Organizer: Chemical Biology Seminar Series, Department of Chemistry, Texas A&M University
  • Int'l Joint Research / Invited
• [Presentation] Transition Metal-Free Tryptophan-Selective Bioconjugation of Proteins (2019)
  • Author(s): Motomu Kanai
  • Organizer: the 257th ACS National meeting & exposition
  • Int'l Joint Research / Invited
• [Presentation] 生体分子の構造変換ダイナミズムへの人工介入を目指した触媒研究 (2019)
  • Author(s): 金井求
  • Organizer: サントリー生命科学財団セミナー
  • Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2019)
  • Author(s): Motomu Kanai
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research / Invited
• [Presentation] 反応開発を基軸とするタンパク質化学修飾 (2019)
  • Author(s): 金井求
  • Organizer: 日本プロセス化学会2019 ウインターシンポジウム
  • Invited
• [Presentation] 生体分子の構造変換ダイナミズムへの人工介入を目指した触媒研究 (2019)
  • Author(s): 金井求
  • Organizer: 京都大学大学院工学研究科、特別講演会
  • Invited
• [Presentation] Synthetic Lysine Acylation of Histones (2018)
  • Author(s): Motomu Kanai
  • Organizer: 10th International Peptide Symposium, Kyoto
  • Int'l Joint Research / Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2018)
  • Author(s): Motomu Kanai
  • Organizer: The 4th International Symposium on Middle Molecular Strategy (ISMMS-4), Tohoku University
  • Int'l Joint Research / Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2018)
  • Author(s): Motomu Kanai
  • Organizer: The University of Tokyo-University of Strasbourg Joint Symposium, Symmetry and Asymmetry in Science, The University of Tokyo
  • Int'l Joint Research / Invited
• [Presentation] 生体分子の構造変換ダイナミズムへの人工介入を目指した触媒研究 (2018)
  • Author(s): 金井求
  • Organizer: 山口大学 IoLセンターシンポジウム
  • Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2018)
  • Author(s): Motomu Kanai
  • Organizer: Chirality 2018, Princeton University
  • Int'l Joint Research / Invited
• [Presentation] 生体分子の構造変換ダイナミズムへの人工介入を目指した触媒研究 (2018)
  • Author(s): 金井求
  • Organizer: 第29回 万有仙台シンポジウム
  • Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2018)
  • Author(s): Motomu Kanai
  • Organizer: Organic & Biomolecular Chemistry Symposium, SIOC, China
  • Int'l Joint Research / Invited
• [Presentation] 旗艦たる触媒化学の創造を求めて (2018)
  • Author(s): 金井求
  • Organizer: 「ハイブリッド触媒」 第1 回 若手道場
  • Invited
• [Presentation] 生体分子を基質とする化学的構造変換法の創出と展開 (2018)
  • Author(s): 金井求
  • Organizer: 創薬生命科学特別講義I、名古屋市立大学
  • Invited
• [Presentation] Aerobic Oxygen-Driven Functionalizations of Proteins (2018)
  • Author(s): Motomu Kanai
  • Organizer: Singapore‐Japan Bilateral Meeting, Nanyang Technological University, Singapore
  • Int'l Joint Research / Invited
• [Remarks] 東京大学大学院薬学系研究科 有機合成化学教室HP
  • URL: http://www.f.u-tokyo.ac.jp/~kanai/index.html
• [Remarks] 金井研HP
  • URL: http://www.f.u-tokyo.ac.jp/~kanai/index.html
• [Remarks] 東京大学大学院薬学系研究科 有機合成化学教室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~kanai/