Screening for selective NFATc4 inhibitors to develop a drug of heart failure

• Project/Area Number: 17K08585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: Kumagai Hidetoshi 東京大学, 医学部附属病院, 特任助教 (20281008)
• Co-Investigator(Kenkyū-buntansha): 池田 祐一 東京大学, 医学部附属病院, 特任准教授 (10744419) ; 東口 治弘 東京大学, 医学部附属病院, 特任准教授 (40436358)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: NFAT / 選択的阻害剤 / ハイスループットスクリーニング / 心不全治療薬

Outline of Final Research Achievements

Our purpose of this study is to identify a selective inhibitor of NFATc4 subtype for the drug development of heart failure. We established a new screening system consisting of a human cell line that requires exogenous Nuclear factor of activated T cells (NFAT) subtypes expression under the angiotensin receptor signaling. By using this new screening system, we tested 269 natural compounds, which are microbial origin, 1270 fungus, and 878 actinomyces metabolites. As a result, we found two fungus metabolites producing selective NFATc4 inhibitory activities then, isolating and identifying the inhibitory activities through large scale cultivation.

Academic Significance and Societal Importance of the Research Achievements

我が国の心不全の患者数は、100万人と推定されており、また、疫学研究によると患者数は 2035年までさらに増加すると予測され、新たな治療法の実用化が急務となっている。心不全はNFATc4活性の亢進が、疾病の発症・進展に重要な分子機序と指摘されていることから、NFATc4の選択的阻害剤は、心不全の新たな薬物療法の開発候補と期待される。本研究課題は、新たにNFATサブタイプの活性を分別定量可能な培養動物細胞株を見出したことで、化合物ライブラリーからNFATc4選択的阻害剤の迅速スクリーニング方法を樹立し、新たな薬物療法開発に繋がる化合物を同定することが可能である。

Research Products

• [Journal Article] Corrigendum to “Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function” [Neuropharmacology 144 (2019) 122?132] (2019)
  • Author(s): Korkutata Mustafa、Saitoh Tsuyoshi、Cherasse Yoan、Ioka Shuji、Duo Feng、Qin Rujie、Murakoshi Nobuyuki、Fujii Shinya、Zhou Xuzhao、Sugiyama Fumihiro、Chen Jiang-Fan、Kumagai Hidetoshi、Nagase Hiroshi、Lazarus Michael
  • Journal Title: Neuropharmacology Volume: 153 Pages: 153-153
  • DOI: 10.1016/j.neuropharm.2019.04.027
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency (2019)
  • Author(s): Takanashi M, Kimura T, Li C, Tanaka M, Matsuhashi A, Yoshida H, Noda A, Xu P, Takase S, Okazaki S, Iizuka Y, Kumagai H, Ikeda Y, Gotoda T, Takahashi M, Yagyu H, Ishibashi S, Yamauchi T, Kadowaki T, Liang G, Okazaki H.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 39 Issue: 3 Pages: 373-386
  • DOI: 10.1161/atvbaha.118.311931
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Bioabsorbable Sheet That Delivers NF-κB Decoy Oligonucleotide Restrains Abdominal Aortic Aneurysm Development in Rats (2018)
  • Author(s): Akimoto Shouta、Suzuki Jun-ichi、Aoyama Norio、Ikeuchi Ryota、Watanabe Hajime、Tsujimoto Hiroyuki、Wakayama Kouji、Kumagai Hidetoshi、Ikeda Yuichi、Akazawa Hiroshi、Komuro Issei
  • Journal Title: International Heart Journal Volume: 59 Issue: 5 Pages: 1134-1141
  • DOI: 10.1536/ihj.17-632
  • NAID: 130007490504
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2018-09-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome (2018)
  • Author(s): Takeda N, Inuzuka R, Maemura S, Morita H, Nawata K, Fujita D, Taniguchi Y, Yamauchi H, Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y, Kumagai H, Amiya E, Hara H, Fujiwara T, Akazawa H, Suzuki JI, Imai Y, Nagai R, Takamoto S, Hirata Y, Ono M, Komuro I.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 11 Issue: 6
  • DOI: 10.1161/circgen.117.002058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys?Dietz syndrome or multiple self-healing squamous epithelioma (2018)
  • Author(s): Fujiwara Takayuki、Takeda Norifumi、Hara Hironori、Morita Hiroyuki、Kishihara Jun、Inuzuka Ryo、Yagi Hiroki、Maemura Sonoko、Toko Haruhiro、Harada Mutsuo、Ikeda Yuichi、Kumagai Hidetoshi、Nomura Seitaro、Takimoto Eiki、Akazawa Hiroshi、Ako Junya、Komuro Issei
  • Journal Title: European Journal of Human Genetics Volume: 26 Issue: 8 Pages: 1151-1158
  • DOI: 10.1038/s41431-018-0127-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Japanese Cardiovascular Disease Patients with Diabetes Mellitus Suffer Increased Tooth Loss in Comparison to Those without Diabetes Mellitus -A Cross-sectional Study (2018)
  • Author(s): Aoyama Norio、Suzuki Jun-ichi、Kobayashi Naho、Hanatani Tomoya、Ashigaki Norihiko、Yoshida Asuka、Shiheido Yuka、Sato Hiroki、Kumagai Hidetoshi、Ikeda Yuichi、Akazawa Hiroshi、Komuro Issei、Minabe Masato、Izumi Yuichi、Isobe Mitsuaki
  • Journal Title: Internal Medicine Volume: 57 Issue: 6 Pages: 777-782
  • DOI: 10.2169/internalmedicine.9578-17
  • NAID: 130006507416
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Periodontitis and myocardial hypertrophy (2017)
  • Author(s): Suzuki J, Sato H, Kaneko M, Yoshida A, Aoyama N, Akimoto S, Wakayama K, Kumagai H, Ikeda Y, Akazawa H, IzumiY, Isobe M, Komuro I
  • Journal Title: Hypertens Res Volume: [Epub ahead of print] Issue: 4 Pages: 324-328
  • DOI: 10.1038/hr.2016.146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A peptide vaccine targeting angiotensin II attenuates the cardiac dysfunction induced by myocardial infarction. (2017)
  • Author(s): Watanabe R, Suzuki JI, Wakayama K, Maejima Y, Shimamura M, Koriyama H, Nakagami H, Kumagai H, Ikeda Y, Akazawa H, Morishita R, Komuro I, Isobe M.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 43920-43920
  • DOI: 10.1038/srep43920
  • Peer Reviewed / Open Access
• [Journal Article] Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. (2017)
  • Author(s): Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, Yagi H, Liu Q, Nomura S, Naito AT, Takeda N, Harada M, Toko H, Kumagai H, Ikeda Y, Takimoto E, Suzuki JI, Honda K, Morita H, Hattori M, Komuro I.
  • Journal Title: PLoS One. Volume: 12 Issue: 3 Pages: 0174099-0174099
  • DOI: 10.1371/journal.pone.0174099
  • Peer Reviewed / Open Access
• [Journal Article] Generation and characterization of an antagonistic monoclonal antibody against an extracellular domain of mouse DP2 (CRTH2/GPR44) receptors for prostaglandin D2 (2017)
  • Author(s): Nagata N, Iwanari H, Kumagai H, Kusano-Arai O, Ikeda Y, Aritake K, Hamakubo T, Urade Y
  • Journal Title: PLoS One Volume: 12 Issue: 4 Pages: 0175452-0175452
  • DOI: 10.1371/journal.pone.0175452
  • NAID: 120007129138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of Hormone-sensitive Lipase in Leptin-Promoted Fat Loss and Glucose Lowering (2017)
  • Author(s): Takanashi M, Taira Y, Okazaki S, Takase S, Kimura T, Li CC, Xu PF, Noda A, Sakata I, Kumagai H, Ikeda Y, Iizuka Y, Yahagi N, Shimano H, Osuga JI, Ishibashi S, Kadowaki T, Okazaki H
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 11 Pages: 1105-1116
  • DOI: 10.5551/jat.39552
  • NAID: 130006191603
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed
• [Journal Article] Periodontitis deteriorates peripheral arterial disease in Japanese population via enhanced systemic inflammation (2017)
  • Author(s): Aoyama N, Suzuki JI, Kobayashi N, Hanatani T, Ashigaki N, Yoshida A, Shiheido Y, Sato H, Kumagai H, Ikeda Y, Akazawa H, Komuro I, Izumi Y, Isobe M
  • Journal Title: Heart Vessels Volume: 32 Issue: 11 Pages: 1314-1319
  • DOI: 10.1007/s00380-017-1003-6
  • Peer Reviewed