Drug discovery targeting Hippo-YAP pathway for heart regeneration

• Project/Area Number: 17K15987
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: The University of Tokyo
• Principal Investigator: HARA Hironori 東京大学, 医学部附属病院, 助教 (60792439)
• Research Collaborator: Takeda Norifumi
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 心筋再生 / Hippo経路 / YAP

Outline of Final Research Achievements

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YAP and TEAD activities in cardiomyocytes. We synthesized a novel fluorine-containing compound (TT-10) from the biologically hit compound. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction. In addition, TT-10 markedly promoted cell cycle activation and increased cell division of human induced pluripotent stem cell-derived cardiomyocytes. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.

Academic Significance and Societal Importance of the Research Achievements

社会の高齢化に伴い、虚血性心疾患・慢性心不全を患う患者数が増加している。既存の虚血性心疾患・慢性心不全に対する治療に、本研究のような「内因性の心筋再生の増幅」を用いた治療を併用することで、これまで以上の治療効果を期待できる。また、化合物による治療は、患者への侵襲・安全性や費用対効果などの点からも有効といえる。本研究の成果は、心疾患による死亡を減らし得るため社会に与える貢献も極めて大きいと考えられる。

Research Products

• [Journal Article] Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes (2019)
  • Author(s): Ito Masamichi、Hara Hironori、Takeda Norifumi、Naito Atsuhiko T.、Nomura Seitaro、Kondo Masaki、Hata Yutaka、Uchiyama Masanobu、Morita Hiroyuki、Komuro Issei
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 128 Pages: 90-95
  • DOI: 10.1016/j.yjmcc.2019.01.020
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury (2018)
  • Author(s): Hara H, Takeda N, Kondo M, Kubota M, Saito T, Maruyama J, Fujiwara T, Maemura S, Ito M, Naito AT, Harada M, Toko H, Nomura S, Kumagai H, Ikeda Y, Ueno H, Takimoto E, Akazawa H, Morita H, Aburatani H, Hata Y, Uchiyama M, Komuro I.
  • Journal Title: JACC: Basic to Translational Science Volume: 3 Issue: 5 Pages: 639-653
  • DOI: 10.1016/j.jacbts.2018.07.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathophysiology and therapeutic potential of cardiac fibrosis (2017)
  • Author(s): Hara Hironori、Takeda Norifumi、Komuro Issei
  • Journal Title: Inflammation and Regeneration Volume: 37 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s41232-017-0046-5
  • Peer Reviewed / Open Access
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury. (2018)
  • Author(s): Hara H, Takeda N, Saito T, Fujiwara T, Maemura S, Hata Y, Uchiyama M, Komuro I
  • Organizer: 第1回日本循環器学会基礎研究フォーラム
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury. (2018)
  • Author(s): Hara H, Takeda N, Saito T, Fujiwara T, Maemura S, Hata Y, Uchiyama M, Komuro I
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Hippo 経路を標的として心筋細胞増殖と心筋再生を増幅する薬剤の開発 (2017)
  • Author(s): 原弘典、武田憲文、斉藤竜男、畑裕、内山真伸、小室一成
  • Organizer: 第54回日本臨床分子医学会学術集会
• [Presentation] Hippo経路を標的として心筋細胞増殖・再生を促進する薬剤の開発 (2017)
  • Author(s): 原弘典、武田憲文、斉藤竜男、藤原隆行、前村園子、畑裕、内山真伸、小室一成
  • Organizer: Molecular Cardiovascular Metabolic Conference 2017
• [Presentation] Discovery of a small molecule to increase cardiomyocytes and protect the heart after ischemic injury. (2017)
  • Author(s): Hara H, Takeda N, Saito T, Fujiwara T, Maemura S, Hata Y, Uchiyama M, Komuro I
  • Organizer: American Heart Association 2017 Scientific Sessions
  • Int'l Joint Research
• [Presentation] 心筋細胞増殖作用と心筋障害への保護作用を併せ持つ新薬創出の試み (2017)
  • Author(s): 原弘典、武田憲文、斉藤竜男、藤原隆行、前村園子、畑裕、内山真伸、小室一成
  • Organizer: 第21回日本心血管内分泌代謝学会学術総会