| Project/Area Number |
14370754
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
ISHIKAWA Toshihisa TOKYO INSTITUTE OF TECHNOLOGY, DEPARTMENT OF BIOFUNCTIONAL ENGINEERING, PROFESSOR, 大学院・生命理工学研究科, 教授 (60193281)
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| Co-Investigator(Kenkyū-buntansha) |
SODEOKA Mikiko TOHOKU UNIVERSITY, INSTITUTE OF MULTIDISCIPLINARY RESEARCH FOR ADVANCED MATERIALS, PROFESSOR, 多元物質科学研究所, 教授 (60192142)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2003: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2002: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Genome-Based Drug Discovery / ABC Transporter / High Speed Screening / Protein Phosphatase / Structure-Activity Relationship / Canser Drug Resistance / Protein Kinase / 光学活性 / カンタリジン / カーバメートライブラリー / ゲノム |
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| Research Abstract |
The ATP-binding cassette(ABC) transporters represent an important mechanism in transport of drugs and their metabolites. Substrate specificity screening of ABC transporters is of great interest to achieve a goal of rational drug molecular design. In this project, we have cloned human novel ABC transporters, such as ABCC11, ABCC12, and ABCC13, and also developed high-speed functional screening systems. By using the Chemical Fragmentation Codes, we have created a new quantitative structure-activity relationship(QSAR) analysis method to study the substrate specificity of ABC transporters. Analysis of the substrate specificity of ABCG2 led us to discovery of new camptothecin (CPT)-based drugs that may circumvent drug-resistance of human cancer. Based on our data, it is strongly suggested that hydrogen bond formation is critically involved in substrate recognition and/or transport processes of ABCG2. Furthermore, we performed structure-based molecular design to discover a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (PP2B/calcineurin). The cantharidin-based inhibitor, thus created, is very potent and specific to PP2B without inhibiting PP1 or PP2A. To our knowledge, this is the first highly selective catalytic-site-directed inhibitor of PP2B. In addition, we have designed novel protein kinase C(PKC) ligands that are as potent as TPA. By structural modifications, we have also succeeded in synthesizing PKC inhibitors that effectively inhibit the invasion of cancer cells.
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