脳を標的とするケミカルバイオロジー:効率的に脳移行する脳腫瘍治療薬の分子デザイン

2009 Fiscal Year Annual Research Report

• Project/Area Number: 18201041
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: 石川 智久 The Institute of Physical and Chemical Research, オミックス基盤研究領域, 客員主管研究員 (60193281)
• Keywords: 癌 / 脳・神経 / 生理活性 / 創薬 / 分子プローブ

Research Abstract

脳腫瘍の治療は容易ではない。その最も大きな理由は、脳という重要な組織に発生しているために、腫瘍が正常脳の中に浸潤した部分を広く切除できないことによる。本研究において、我々は血液脳関門に発現しているABCトランスポーター(ABCB1,ABCG2等)の基質にならず、効率的に脳移行する新規脳腫瘍治療薬の分子デザインを試行した。また、これらトランスポーターを阻害する薬をデザインし、制癌剤が脳腫瘍に到達できるようにした。平成21年度、我々は独自に開発した定量的構造活性相関(QSAR)解析法を用いて、ABCG2の基質になる化学的構造要素を導出し、ABCG2を強力に阻害するプロテインキナーゼ阻害剤を見出し、分子軌道計算と3次元QSAR解析を実施した(Saito H, et al.Emerging new technology : QSAR analysis and Mo calculation to charactedze the interaction of protein kinase inhibitors with human ABC transporter ABCG2(BCRP)Drug Metab. pharmacokin., in press, 2010)。また、脳腫瘍の光線力学療法においてABCG2が重要な役割を担っていることを実際の悪性脳腫瘍glioma患者の組織を用いた遺伝子発現プロファイリングによって証明した(Ishikawa T, et al.Key role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis.Adv.Pharm.Sci, inpress,2010)。さらに、ABCG2を強く阻害するプロテインキナーゼ阻害薬が、脳腫瘍の光線力学療法の効果を向上させることもin vitro系で実証した。

Research Products

• [Journal Article] Key role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis (2010)
  • Author(s): Ishikawa T, Nakagawa H, Hagiya Y, Nonoguchi N, Miyatake S, Kuroiwa T.
  • Journal Title: Advances in Pharmacological Sciences (印刷中)
  • Peer Reviewed
• [Journal Article] Emerging new technology : QSAR analysis and MO calculation to characterize the interaction of protein kinase inhibitors with human ABC tran sporter ABCG2(BCRP) (2010)
  • Author(s): Saito H, An R, Hirano H., Ishikawa T.
  • Journal Title: Drug Metabolism and Pharmacokinetics (印刷中)
  • Peer Reviewed
• [Journal Article] Emerging new technologies in pharmacogenomics : Rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1(P-gp/MDR1) (2010)
  • Author(s): Ishikawa T., Sakurai A, Hirano H, Lezhava A, Sakurai M, Hayashizaki Y
  • Journal Title: Pharmacology and Therapeutics (印刷中)
  • Peer Reviewed
• [Journal Article] QSAR analysis and MO calculation to predict drug interactions with human ABC transporter ABCG2 (2010)
  • Author(s): Saito H, Ishikawa T.
  • Journal Title: Current Trends in Medicinal Chemistry (印刷中)
  • Peer Reviewed
• [Journal Article] Transport-metabolism interplay : LXRa-mediated induction of human ABC transporter ABCC2(cMOAT/MRP2)in HepG2 cells (2009)
  • Author(s): Adachi T, Nakagawa H, Hagiya H, Yasuoka T, Ishikawa T.
  • Journal Title: Molecular Pharmaceutics 6 Pages: 1678-1688
  • Peer Reviewed
• [Journal Article] Technical pitfalls and improvements in high-speed screening and QSAR analysis to predict durg-drug interactions of ABC transporter ABCB11(bile salt export pump) (2009)
  • Author(s): Saito H, Hirano H, Wangsoo Shin, Nakamura R, Osumi M, Ishikawa T.
  • Journal Title: AAPS Journal 11 Pages: 581-589
  • Peer Reviewed
• [Journal Article] Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro (2009)
  • Author(s): An R, Hagiya Y, Tamura A, Li S, Saito H, Tokushima D, Ishikawa T.
  • Journal Title: Pharmaceutical Research 26 Pages: 449-458
  • Peer Reviewed
• [Journal Article] Cellular phototoxicity evoked through the inhibition of human ABC transporter ABCG2 by cyclin-dependent kinase inhibitors in vitro (2009)
  • Author(s): An R, Hagiya Y, Tamura A, Li S, Saito H, Ishikawa T.
  • Journal Title: PORPHYRINS 8 Pages: 7-12
• [Journal Article] Role of Nrf2 in the induction of human ABC transporter ABCG2 and hemeoxygenase-1 in HepG2 cells via photoactivation of porphyrins (2009)
  • Author(s): Hagiya Y, Adachi T, Okura S, An R, Tamura A, Nakagawa H, Mochizuki T, Ishikawa T.
  • Journal Title: PORPHYRINS 8 Pages: 12-18
• [Journal Article] 天然物及び食品添加物による細胞内レドックス制御機構の温故知新 (2009)
  • Author(s): 足立達彦、萩谷祐一郎、中川大、石川智久
  • Journal Title: Foods Food Ingredients Jounal of Japan 214 Pages: 35-47
• [Journal Article] (2009)
  • Author(s): 石川智久
  • Journal Title: 薬物トランスポーター活用ライブラリー(乾賢一・編)(羊土社) Pages: 136-139
• [Journal Article] (2009)
  • Author(s): 石川智久
  • Journal Title: 薬物トランスポーター活用ライブラリー(乾賢一・編)(羊土社) Pages: 158-163
• [Presentation] Phamacogenomics of human ABC transporters : from functional validation to chnical application (2010)
  • Author(s): Ishikawa, T., Aw, W., Saito, H., Toyoda, Y., Nakagawa, H., Lezhava, A., Hayashizaki, Y.
  • Organizer: 3^<rd> FEBS Special Meeting on ABC Proteins
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 2010-03-04
• [Presentation] QSAR-based prediction and identification of novel dual inhibitors against ABCG2/BCRP and protein kinases (2010)
  • Author(s): Saito, H., Hirano, H., Ishikawa, T.
  • Organizer: 3^<rd> FEBS Special Meeting on ABC Proteins
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 2010-03-04
• [Presentation] Three-Dimensional SAR analysis of protein kinase inhibitors identified by QSAR analysis of human ABC transporter ABCG2 (2009)
  • Author(s): Saito, H., Nakagawa, H, Ishikawa, T.
  • Organizer: 日本がん学会総会
  • Place of Presentation: (パシフィコ横浜)横浜
  • Year and Date: 2009-10-03
• [Presentation] Nrf2-dependent Induction of Human ABC Transporter ABCG2 and Heme oxygenase-1 in HepG2 cells by Photoactivation of Porphirins : Biochemical Implications for Cancer Cell Response to Photodynamic Therapy (2009)
  • Author(s): Hagiya, Y., Adachi, T., Ogura, S, An, R., Tamura, I., Nakagawa, H., Okura, I., Mochizuki, T., Ishikawa, T.
  • Organizer: The 5^<th> Takeda Science Foundation Symposium on PharmaSciences, Tokyo, Japan
  • Place of Presentation: (GRAND PRINCE HOTEL TAKANAWA)東京
  • Year and Date: 2009-05-25
• [Presentation] Identification and Inhibitory Characterization of Protein Kinase Inhibitors Based on QSAR Analysis of Human ABC Transporter ABCG2 (2009)
  • Author(s): Saito, H., Hirano, H., Ishikawa, T.
  • Organizer: The 5^<th> Takeda Science Foundation Symposium on PharmaSciences, Tokyo, Japan
  • Place of Presentation: (GRAND PRINCE HOTEL TAKANAWA)東京
  • Year and Date: 2009-05-25