Activation of HIF by inhibiting FIH: the development of novel organic molecules inhibiting FIH selectively

• Project/Area Number: 26860168
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Saga University (2015-2016); Tohoku University (2014)
• Principal Investigator: Kawaguchi Shin-ichi 佐賀大学, 農学部, 特任助教 (00722894)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: HIF / 低酸素誘導因子 / FIH / 低分子阻害剤 / 構造活性相関 / 低分子化合物 / ドッキングシミュレーション / 虚血性疾患治療薬

Outline of Final Research Achievements

In this study, the exploration of novel organic molecules inhibiting FIH (Factor Inhibiting HIF) was conducted because previous studies shows that HIF (hypoxia inducible factor: transcription factor) can be gently activated by inhibiting FIH. The gentle activation of HIF is effective for the treatment of ischemic disease. The research group synthesized about 70 compounds and a few compounds of them induced gentle activation of HIF.

Research Products

• [Journal Article] P-Fluorous Phosphines as Electron-Poor/Fluorous Hybrid Functional Ligands for Precious Metal Catalysts: Synthesis of Rh(I), Ir(I), Pt(II), and Au(I) Complexes Bearing P-Fluorous Phosphine Ligands (2017)
  • Author(s): Kawaguchi, S-i.; Saga, Y.; Sato, Y.; Minamida, Y.; Nomoto, A.; Ogawa, A.
  • Journal Title: Inorganics Volume: 5 Issue: 1 Pages: 5-5
  • DOI: 10.3390/inorganics5010005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Highly Selective Phosphinylphosphination of Alkenes with Tetraphenyldiphosphine Monoxide (2016)
  • Author(s): Sato, Y.; Kawaguchi, S-i.; Nomoto, A.; Ogawa, A.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 55 Issue: 33 Pages: 9700-9703
  • DOI: 10.1002/anie.201603860
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Discovery of an NRF1-specific inducer from a large-scale chemical library using a direct NRF1-protein monitoring system. (2015)
  • Author(s): Tsujita T, Baird L, Furusawa Y, Katsuoka F, Hou Y, Gotoh S, Kawaguchi S-i, and Yamamoto M.
  • Journal Title: Genes Cells Volume: 7 Issue: 7 Pages: 563-577
  • DOI: 10.1111/gtc.12248
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hypoxia-Sensitive Reporter System for High-Throughput Screening (2015)
  • Author(s): Tsujita, T.; Kawaguchi, S-i.; Dan, T.; Baird, L.; Miyata, T.; Yamamoto, M.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 235 Issue: 2 Pages: 151-159
  • DOI: 10.1620/tjem.235.151
  • NAID: 130004822440
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 2-カルボニルフラン誘導体によるHIFの活性化およびその活性化経路の検討 (2016)
  • Author(s): 川口真一・辻田忠志・小川昭弥・宮田敏男
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] HIF(低酸素誘導因子)活性化剤の設計と合成およびその活性評価 (2016)
  • Author(s): 川口真一・辻田忠志・宮田敏男・小川昭弥
  • Organizer: 第40回 蛋白質と酵素の構造と機能に関する九州シンポジウム
  • Place of Presentation: 指宿ベイテラス
  • Year and Date: 2016-08-26
• [Presentation] フランおよびチオフェン-2-カルボニルアミノ酸誘導体によるfactor of inhibiting HIF(FIH)阻害 (2015)
  • Author(s): 川口真一・辻田忠志 ・ 宮田敏男 ・小川昭弥
  • Organizer: 第13回がんとハイポキシア研究会
  • Place of Presentation: 国立遺伝学研究所
  • Year and Date: 2015-06-05