| Project/Area Number |
11694297
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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 | Kumamoto University |
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Principal Investigator |
OTSUKA Masami Kumamoto University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (40126008)
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| Co-Investigator(Kenkyū-buntansha) |
OKAMOTO Yoshinari Kumamoto University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 助手 (20194409)
YAMASAKI Tetsuo Kumamoto University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 助手 (60182474)
OKAWARA Tadashi Kumamoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究科, 助教授 (60040325)
IMOTO Masaya Keio University, Faculty of Science and Technology, Associate Professor, 理工学部, 助教授 (60213253)
UMEZAWA Kazuo Keio University, Faculty of Science and Technology, Professor, 理工学部, 教授 (70114402)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥9,100,000 (Direct Cost: ¥9,100,000)
Fiscal Year 2001: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2000: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1999: ¥3,200,000 (Direct Cost: ¥3,200,000)
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| Keywords | man-made chelator / farnesyltransferase / oncogene / Ras protein |
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| Research Abstract |
Oncogene ras is found in many mammalian cancer cells and the encoded protein Ras is an important target for anticancer agents. The farnesylation of the terminal cystein residue of the Ras protein by farnesyltransferase (FTase) is essential for the function of the Ras protein.
Considering that the Ras protein is a zinc enzyme, the objective of the present research is to design and synthesize zinc chelating agents to find novel inhibitors of FTase by a collaboration of synthetic organic chemists, FTase enzymologists, and researchers of oncogene and cellular signaling.
In 2001 a diversified research was carried out by the participation of US colleagues, Fuyuhiko Tamanoi (University of California, Los Angeles), Terrence R. Burke (National Institute of Health), Patrick J. Casey (Duke University), David R. Corey (University of Texas Southwestern Medical Center at Dallas), John S. Lazo(University of Pittsburgh), Veeraswamy Manne (Bristol-Myers Squibb Pharmaceutical Research Institute) in addition to the Investigators of this project, Otsuka, Okawara, Yamasaki, Okamoto, Umezawa, and Imoto. An international symposium (US-Japan Joint Symposium on Chemistry-Biology Interface) was held in Kumamoto (July 27 and 28, 2001) to report and discuss the research results of the present research project.
The results of 2001 were summarized as follows : (i) Farnesyltransferase mutants were inhibited by various synthetic chelators consisting of a dimethylaminopyridine and histamine side chains, (ii) A histidine-pyridine-histidine ligand was found to be a useful as a sensitizer for the hyperthermic treatment of cancer cell lines. (iii) The relationships betweenthe farnesylation of Ras and farnesyltransferase were elucidated, (iv) Clinical application of farnesyltransferase inhibitors was studied, (v) Inhibitors of Grb2SH domain were synthesized.
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