Development and characterization of small molecules for analysis of circadian rhythm amplitude

• Project/Area Number: 18K19171
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 38:Agricultural chemistry and related fields
• Research Institution: Nagoya University
• Principal Investigator: Hirota Tsuyoshi 名古屋大学, トランスフォーマティブ生命分子研究所, 特任准教授 (50372412)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 概日時計 / ケミカルバイオロジー / 化合物 / 振幅

Outline of Final Research Achievements

Amplitude of the circadian rhythm is reduced by metabolic disease and aging. While circadian amplitude plays an important role in the regulation of physiological outputs, its molecular mechanism is poorly understood. In this study, we tried to approach the molecular mechanism of circadian amplitude regulation by applying chemical biology methods. From chemical screening, we identified new compounds that increase rhythm amplitude and analyzed its mechanism of action. Further study will facilitate the understanding of amplitude regulation.

Academic Significance and Societal Importance of the Research Achievements

本研究により、振幅を増加させる新規化合物を発見した。このようなユニークな化合物が起点となり、将来的には概日リズム疾患の治療への応用に繋がる可能性が期待される。さらに、ケージドlongdaysinを開発して光を用いて概日リズム周期を誘導的かつ精密に調節することを世界で初めて実現し、chronophotopharmacologyという新領域を切り拓いた。

Research Products

• [Int'l Joint Research] University of Southern California/University of California Santa Cruz/California Institute of Technology(米国)
• [Int'l Joint Research] University of Groningen(オランダ)
• [Int'l Joint Research] University of Southern California/The Scripps Research Institute(米国)
• [Int'l Joint Research] Korea Inst Sci Tech(韓国)
• [Journal Article] Isoform-selective regulation of mammalian cryptochromes (2020)
  • Author(s): Miller Simon、Son You Lee、Aikawa Yoshiki、Makino Eri、Nagai Yoshiko、Srivastava Ashutosh、Oshima Tsuyoshi、Sugiyama Akiko、Hara Aya、Abe Kazuhiro、Hirata Kunio、Oishi Shinya、Hagihara Shinya、Sato Ayato、Tama Florence、Itami Kenichiro、Kay Steve A.、Hatori Megumi、Hirota Tsuyoshi
  • Journal Title: Nature Chemical Biology Volume: - Issue: 6 Pages: 676-685
  • DOI: 10.1038/s41589-020-0505-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing (2020)
  • Author(s): Fribourgh Jennifer L、Srivastava Ashutosh、Sandate Colby R、Michael Alicia K、Hsu Peter L、Rakers Christin、Nguyen Leslee T、Torgrimson Megan R、Parico Gian Carlo G、Tripathi Sarvind、Zheng Ning、Lander Gabriel C、Hirota Tsuyoshi、Tama Florence、Partch Carrie L
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.55275
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological Interventions to Circadian Clocks and Their Molecular Bases (2020)
  • Author(s): Miller Simon、Hirota Tsuyoshi
  • Journal Title: Journal of Molecular Biology Volume: - Issue: 12 Pages: 3498-3514
  • DOI: 10.1016/j.jmb.2020.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Controlling the Circadian Clock with High Temporal Resolution through Photodosing (2019)
  • Author(s): Kolarski Dusan、Sugiyama Akiko、Breton Ghislain、Rakers Christin、Ono Daisuke、Schulte Albert、Tama Florence、Itami Kenichiro、Szymanski Wiktor、Hirota Tsuyoshi、Feringa Ben L.
  • Journal Title: Journal of the American Chemical Society Volume: 141 Issue: 40 Pages: 15784-15791
  • DOI: 10.1021/jacs.9b05445
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of pathways that regulate circadian rhythms using a larval zebrafish small molecule screen (2019)
  • Author(s): Mosser Eric A.、Chiu Cindy N.、Tamai T. Katherine、Hirota Tsuyoshi、Li Suna、Hui May、Wang Amy、Singh Chanpreet、Giovanni Andrew、Kay Steve A.、Prober David A.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12405-12405
  • DOI: 10.1038/s41598-019-48914-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemical Synthesis of Atomically Tailored SUMO E2 Conjugating Enzymes for the Formation of Covalently Linked SUMO?E2?E3 Ligase Ternary Complexes (2019)
  • Author(s): Zhang Yinfeng、Hirota Tsuyoshi、Kuwata Keiko、Oishi Shunsuke、Gramani Subramanian G.、Bode Jeffrey W.
  • Journal Title: Journal of the American Chemical Society Volume: 141 Issue: 37 Pages: 14742-14751
  • DOI: 10.1021/jacs.9b06820
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock (2019)
  • Author(s): Uehara TN.、Mizutani Y、Kuwata K、Hirota T、Sato A、Mizoi J、Takao S、Matsuo H、Suzuki T、Ito S、Saito AN.、Nishiwaki-Ohkawa T、Yamaguchi-Shinozaki K、Yoshimura T、Kay SA.、Itami K、Kinoshita T、Yamaguchi J、Nakamichi N.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 23 Pages: 11528-11536
  • DOI: 10.1073/pnas.1903357116
  • NAID: 120006645300
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth. (2019)
  • Author(s): Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T.
  • Journal Title: Science Advance Volume: 23 Issue: 1 Pages: 9060-9060
  • DOI: 10.1126/sciadv.aau9060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemical Control of Mammalian Circadian Behavior through Dual Inhibition of Casein Kinase Iα and δ (2019)
  • Author(s): Lee Jae Wook、Hirota Tsuyoshi、Ono Daisuke、Honma Sato、Honma Ken-ichi、Park Keunwan、Kay Steve A.
  • Journal Title: Journal of Medicinal Chemistry Volume: 62 Issue: 4 Pages: 1989-1998
  • DOI: 10.1021/acs.jmedchem.8b01541
  • NAID: 120006645104
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 時計遺伝子から考える脳機能と食 (2019)
  • Author(s): 羽鳥 恵、廣田 毅
  • Journal Title: FOOD Style21 Volume: 23 Pages: 80-83
• [Journal Article] Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks (2018)
  • Author(s): Qu Meng、Duffy Tomas、Hirota Tsuyoshi、Kay Steve A.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 52
  • DOI: 10.1073/pnas.1816411115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Small molecule modulators of the circadian clock function (2020)
  • Author(s): Tsuyoshi Hirota
  • Organizer: 日本薬理学会 第93回年会
  • Invited
• [Presentation] 哺乳類CRYタンパク質のアイソフォーム選択的な制御 (2019)
  • Author(s): 廣田 毅
  • Organizer: 第2回構造生命科学研究会
• [Presentation] 概日時計タンパク質を標的とする低分子化合物 (2019)
  • Author(s): 廣田 毅
  • Organizer: 2019年度BINDS公開シンポジウム
  • Invited
• [Presentation] Chemical and structural biology approach for circadian biochemistry of clock proteins (2019)
  • Author(s): Tsuyoshi Hirota
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] Small molecule modulators of mammalian clock proteins (2019)
  • Author(s): Tsuyoshi Hirota
  • Organizer: 2019 CIBR Beijing Conference on Brain & Behavior
  • Int'l Joint Research / Invited
• [Presentation] 体内時計を調節する化合物の探索 (2019)
  • Author(s): 廣田 毅
  • Organizer: 日本農芸化学会2019年度大会
  • Invited
• [Presentation] 構造生物学とケミカルバイオロジーの融合による概日時計の創薬研究 (2019)
  • Author(s): 廣田 毅
  • Organizer: 蛋白研セミナー 第1回構造生命科学研究会
  • Invited
• [Presentation] 新規の概日リズム調節化合物の同定とがん細胞増殖に対する効果 (2019)
  • Author(s): 廣田 毅
  • Organizer: 第2回がんと代謝研究会若手の会
• [Presentation] Dissecting mammalian clock mechanism with chemical tools (2018)
  • Author(s): Hirota, T.
  • Organizer: International Symposium on Biological Rhythms
  • Int'l Joint Research / Invited
• [Presentation] ケミカルバイオロジーを応用した哺乳類の概日時計のメカニズム解析 (2018)
  • Author(s): 廣田 毅
  • Organizer: 第3回先端ケミカルバイオロジー研究会
  • Invited
• [Presentation] Identification of CRY1/CRY2 selective compounds (2018)
  • Author(s): Hirota, T.
  • Organizer: 2018 Society for Research on Biological Rhythm Meeting
  • Int'l Joint Research
• [Remarks] 名古屋大学トランスフォーマティブ生命分子研究所Kay-廣田グループ
  • URL: http://www.itbm.nagoya-u.ac.jp/ja/kay-hirota_group/