Development of inhibitors that stablize the transition state of enzymatic reactions

• Project/Area Number: 16KT0060
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Transition State Control
• Research Institution: Osaka University (2019-2020); Kyoto Prefectural University of Medicine (2016-2018)
• Principal Investigator: Suzuki Takayoshi 大阪大学, 産業科学研究所, 教授 (90372838)
• Project Period (FY): 2016-07-19 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 遷移状態 / 酵素 / 阻害薬 / 速度論的阻害薬 / アイソザイム選択性 / 薬学 / 有機化学

Outline of Final Research Achievements

We have identifed isozyme-selective KDAC inhibitors that stablize the transition state of enzymatic reactions by the construction of a 2-aminoanilide compound library, kinetic screening and isozyme selectivity evaluation of the hit compounds. These inhibitors showed potent pharmacological effects such as memory-enhancing activity.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会を迎えた日本では、がんやアルツハイマー病など、未だ特効薬の無い疾患が多数存在する。本研究により、酵素反応の遷移状態構造を考慮することにより、将来の医薬品につながる阻害剤の創製が可能であることが示された。本研究の成果は、アンメットメディカルニーズの高い疾患の治療につながることが期待される。

Research Products

• [Int'l Joint Research] Nirma University(インド)
• [Journal Article] Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors (2021)
  • Author(s): Gediya P, Vyas V K, Carafa V, Sitwala N, Torre L D, Poziello A, Kurohara, T Suzuki T, Raghuraman V, Suthindhiran K, Ghosh D, Bhatia D, Altucci L, Manjunath D
  • Journal Title: Ghate Bioorg Chem Volume: 110 Pages: 104801-104819
  • DOI: 10.1016/j.bioorg.2021.104801
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Downregulation of the Ca2+-activated K+ channel KCa3.1 in mouse preosteoblast cells treated with vitamin D receptor agonist (2020)
  • Author(s): Kito Hiroaki、Morihiro Haruka、Sakakibara Yuka、Endo Kyoko、Kajikuri Junko、Suzuki Takayoshi、Ohya Susumu
  • Journal Title: American Journal of Physiology-Cell Physiology Volume: 319 Issue: 2 Pages: C345-C358
  • DOI: 10.1152/ajpcell.00587.2019
  • NAID: 130007902073
  • Peer Reviewed
• [Journal Article] Discovery of gamma-mangostin from Garcinia mangostana as a potent and selective natural SIRT2 inhibitor (2020)
  • Author(s): Yeong Keng Yoon、Khaw Kooi Yeong、Takahashi Yukari、Itoh Yukihiro、Murugaiyah Vikneswaran、Suzuki Takayoshi
  • Journal Title: Bioorganic Chemistry Volume: 94 Pages: 103403-103403
  • DOI: 10.1016/j.bioorg.2019.103403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] エピゲノム修飾薬 (2020)
  • Author(s): 鈴木孝禎
  • Journal Title: 遺伝子医学 Volume: 31 Pages: 74-79
• [Journal Article] Early sirtuin 2 inhibition prevents age-related cognitive decline in a senescence-accelerated mouse model (2019)
  • Author(s): Diaz-Perdigon Teresa、Belloch Francisco B.、Ricobaraza Ana、Elboray Elghareeb E.、Suzuki Takayoshi、Tordera Rosa M.、Puerta Elena
  • Journal Title: Neuropsychopharmacology Volume: 45 Issue: 2 Pages: 347-357
  • DOI: 10.1038/s41386-019-0503-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Possible Contribution of Inflammation-Associated Hypoxia to Increased K2P5.1 K+ Channel Expression in CD4+ T Cells of the Mouse Model for Inflammatory Bowel Disease (2019)
  • Author(s): Endo Kyoko、Kito Hiroaki、Tanaka Ryo、Kajikuri Junko、Tanaka Satoshi、Elboray Elghareeb E.、Suzuki Takayoshi、Ohya Susumu
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 1 Pages: 38-38
  • DOI: 10.3390/ijms21010038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Diketopiperazine-Containing 2-Anilinobenzamides as Potent Sirtuin 2 (SIRT2)-Selective Inhibitors Targeting the “Selectivity Pocket”, Substrate-Binding Site, and NAD+-Binding Site (2019)
  • Author(s): Mellini Paolo、Itoh Yukihiro、Elboray Elghareeb E.、Tsumoto Hiroki、Li Ying、Suzuki Miki、Takahashi Yukari、Tojo Toshifumi、Kurohara Takashi、Miyake Yuka、Miura Yuri、Kitao Yuki、Kotoku Masayuki、Iida Tetsuya、Suzuki Takayoshi
  • Journal Title: Journal of Medicinal Chemistry Volume: 62 Issue: 12 Pages: 5844-5862
  • DOI: 10.1021/acs.jmedchem.9b00255
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HDAC8 inhibition ameliorates pulmonary fibrosis (2019)
  • Author(s): Shigeki Saito, Yan Zhuang, Takayoshi Suzuki, Yosuke Ota, Marjorie E. Bateman, Ala L. Alkhatib, Gilbert F. Morris and Joseph A. Lasky
  • Journal Title: American Journal of Physiology Lung Cellular and Molecular Physiology Volume: 316 Issue: 1 Pages: L175-L186
  • DOI: 10.1152/ajplung.00551.2017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Computational analysis for selectivity of histone deacetylase inhibitor by replica-exchange umbrella sampling molecular dynamics simulations (2018)
  • Author(s): Tsukamoto Shuichiro、Sakae Yoshitake、Itoh Yukihiro、Suzuki Takayoshi、Okamoto Yuko
  • Journal Title: The Journal of Chemical Physics Volume: 148 Issue: 12 Pages: 125102-125102
  • DOI: 10.1063/1.5019209
  • NAID: 120006545081
  • Peer Reviewed
• [Journal Article] HDAC8 regulates neural differentiation through embryoid body formation in P19 cells (2018)
  • Author(s): Syouichi Katayama, Atsushi Morii, Juliet O. Makanga, Takayoshi Suzuki, Naoki Miyata and Tetsuya Inazu
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 498 Issue: 1 Pages: 45-51
  • DOI: 10.1016/j.bbrc.2018.02.195
  • Peer Reviewed
• [Journal Article] Structural basis of HDAC8 selective inhibition (2018)
  • Author(s): M. Marek, T. B. Shaik, T. Heimburg, A. Chakrabarti, J. Lancelot, E. Ramos-Morales, C. Da Veiga, D. Kalinin, J. Melesina, D. Robaa, K. Schmidtkunz, T. Suzuki, R. Holl, E. Ennifar, R. J. Pierce, M. Jung, W. Sippl and C. Romier
  • Journal Title: Journal of Medicinal Chemistry Volume: 61 Issue: 22 Pages: 10000-10016
  • DOI: 10.1021/acs.jmedchem.8b01087
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene. (2017)
  • Author(s): Uchida S, Teubner BJ, Hevi C, Hara K, Kobayashi A, Dave RM, Shintaku T, Jaikhan P, Yamagata H, Suzuki T, Watanabe Y, Zakharenko SS, Shumyatsky GP.
  • Journal Title: Cell Rep Volume: 18 Issue: 2 Pages: 352-366
  • DOI: 10.1016/j.celrep.2016.12.052
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Medicinal Chemistry Insights into Novel HDAC Inhibitors: An Updated Patent Review (2012-2016) (2017)
  • Author(s): Peng Zhan, Xueshun Wang, Xinyong Liu, Takayoshi Suzuki
  • Journal Title: Recent Patents Anticancer Drug Discovery Volume: 12 Issue: 1 Pages: 16-34
  • DOI: 10.2174/1574892811666161101102842
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Identification of Epigenetic Inhibitors by Target-Guided Synthesis (2020)
  • Author(s): Takayoshi Suzuki
  • Organizer: Academia Sinica-Osaka University Symposium 2020
  • Int'l Joint Research / Invited
• [Presentation] Discovery of Epigenetic Inhibitors Using Target-Guided Synthesis (2019)
  • Author(s): Takayoshi Suzuki
  • Organizer: The 4th Roundtable Meeting on Chemical Probe Research Hub
  • Int'l Joint Research / Invited
• [Presentation] Chemical Control of Epigenetics~Discovery of Histone Lysine Demethylase Inhibitors and Histone Deacetylase Inhibitors~ (2019)
  • Author(s): Takayoshi Suzuki
  • Organizer: Lecture in Global Frontiers in Life Science A, Kyoto University
  • Int'l Joint Research / Invited
• [Presentation] Chemical Control of Epigenetics for the Treatment of Cancers and Neurological Disorders (2019)
  • Author(s): Takayoshi Suzuki
  • Organizer: The 27th French-Japanese Symposium on Medicinal and Fine Chemistry
  • Int'l Joint Research / Invited
• [Presentation] Chemical Control of Epigenetics for the Treatment of Diseases (2018)
  • Author(s): Takayoshi Suzuki
  • Organizer: ICPAC Langkawi 2018
  • Int'l Joint Research / Invited
• [Presentation] エピジェネティクスを標的とした創薬研究 (2017)
  • Author(s): 鈴木孝禎
  • Organizer: Kyoto University MIC/SK-Project Seminar
  • Place of Presentation: 京都
  • Year and Date: 2017-02-03
  • Invited
• [Presentation] エピジェネティクス制御に基づいた創薬研究 (2017)
  • Author(s): 鈴木孝禎
  • Organizer: 京都工芸繊維大学昆虫先端研究推進拠点シンポジウム
  • Invited
• [Presentation] ヒストンアセチル化/メチル化を標的とした創薬研究 (2017)
  • Author(s): 鈴木孝禎
  • Organizer: 千葉大学 再生システムと疾患・癌エピゲノム公開シンポジウム
  • Invited
• [Presentation] Discovery of isozyme-selective lysine demethylase inhibitors and deacetylase inhibitors (2017)
  • Author(s): Takayoshi Suzuki
  • Organizer: AIMECS2017
  • Int'l Joint Research / Invited
• [Presentation] 化学の力で難治性疾患に挑む ～エピジェネティクス創薬化学～ (2016)
  • Author(s): 鈴木孝禎
  • Organizer: 第6回CSJ化学フェスタ2016
  • Place of Presentation: 東京
  • Year and Date: 2016-11-16
  • Invited
• [Presentation] エピジェネティクス制御因子阻害剤の創製とその応用 (2016)
  • Author(s): 鈴木孝禎
  • Organizer: 第３８回日本生物学的精神医学会・第５９回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-09
  • Invited
• [Remarks] 大阪大学産業科学研究所複合分子化学研究分野ホームページ
  • URL: https://www.sanken.osaka-u.ac.jp/labs/cmc/
• [Remarks] 京都府立医科大学大学院医学研究科 医薬品化学
  • URL: http://www.f.kpu-m.ac.jp/y/chemistry/
• [Patent(Industrial Property Rights)] 炎症性腸疾患処置剤 (2020)
  • Inventor(s): 長谷耕二、高橋大輔、鈴木 孝禎、黒原 崇、上田 聡、田中 啓太
  • Industrial Property Rights Holder: 長谷耕二、高橋大輔、鈴木 孝禎、黒原 崇、上田 聡、田中 啓太
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-064635
  • Filing Date: 2020
• [Patent(Industrial Property Rights)] ヒストン脱アセチル化酵素阻害剤 (2018)
  • Inventor(s): 鈴木孝禎、伊藤幸裕、東條敏史、内田周作
  • Industrial Property Rights Holder: 鈴木孝禎、伊藤幸裕、東條敏史、内田周作
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-008464
  • Filing Date: 2018