Development and biological evaluation of small molecule inhibitors for Met using a new strategy
Project/Area Number |
23300365
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Clinical oncology
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Research Institution | National Defense Medical College |
Principal Investigator |
SHINOMIYA Nariyoshi 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 医学教育部医学科専門課程, 教授 (40505260)
|
Co-Investigator(Kenkyū-buntansha) |
TANUMA Sei-ichi 東京理科大学, 薬学部・生化学, 教授 (10142449)
|
Co-Investigator(Renkei-kenkyūsha) |
MORIMOTO Yuji 防衛医科大学校, 医学教育部専門課程, 准教授 (10449069)
MATSUO Hirotaka 防衛医科大学校, 医学教育部専門課程, 講師 (00528292)
|
Project Period (FY) |
2011-04-01 – 2014-03-31
|
Project Status |
Completed (Fiscal Year 2013)
|
Budget Amount *help |
¥21,970,000 (Direct Cost: ¥16,900,000、Indirect Cost: ¥5,070,000)
Fiscal Year 2013: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Fiscal Year 2011: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
|
Keywords | Met / 分子標的薬 / Imatinib / COSMOS法 / リード化合物 / ホモロジーモデリング / Hot spot / Kinase活性 |
Research Abstract |
Met tyrosine kinase transduces multifunctional signals that enhance tumor progression, invasion, and angiogenesis. Also Met correlates well with poor prognosis in clinical cancers. Therefore, Met is considered to be a suitable molecule for targeting therapy. Introducing our new strategy named COSMOS (Conversion to Small Molecules through Optimized-Peptides Strategy), we have designed candidate molecules for Met inhibitors. Main strategic concept of the drug design for Met was based on its similarity to the tertiary structure of T315I-mutated type Bcr-Abl. Among various molecules tested, two compounds inhibited Met kinase activity most effectively, thereby showing the possibility of becoming candidate lead compounds. We also developed oligopeptides that can bind Met kinase and effectively inhibits its activity. These results provide information about a new strategy for developing small molecule inhibitors for Met.
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Report
(4 results)
Research Products
(132 results)
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[Journal Article] Common variants of a urate-associated gene LRP2 are not associated with gout susceptibility2014
Author(s)
Nakayama, A. Matsuo, H. Shimizu, T. Takada, Y. Nakamura, T. Shimizu, S. Chiba, T. Sakiyama, M. Naito, M. Morita, E. Ichida, K. Shinomiya, N.
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Journal Title
Rheumatol Int
Volume: 34(4)
Issue: 4
Pages: 473-6
DOI
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Peer Reviewed
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[Journal Article] A common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility2014
Author(s)
Sakiyama, M. Matsuo, H. Shimizu, S. Chiba, T. Nakayama, A. Takada, Y. Nakamura, T. Takada, T. Morita, E. Naito, M. Wakai, K. Inoue, H. Tatsukawa, S. Sato, J. Shimono, K. Makino, T. Satoh, T. Suzuki, H. Kanai, Y. Hamajima, N. Sakurai, Y. Ichida, K. Shimizu, T. Shinomiya, N.
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Journal Title
Hum Cell
Volume: 27(1)
Issue: 1
Pages: 1-4
DOI
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Peer Reviewed
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[Journal Article] Overexpression of HGF Promotes HBV-Induced Hepatocellular Carcinoma Progression and Is an Effective Indicator for Met-Targeting Therapy2013
Author(s)
Xie Q., Su Y., Dykema K., Johnson J., Koeman J., De Giorgi V., Huang A., Schlegel R., Essenburg C., Kang L., Iwaya K., Seki S., Khoo S.K., Zhang B., Buonaguro F., Marincola F. M., Furge K., Vande Woude G.F., and Shinomiya N
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Journal Title
Genes Cancer
Volume: 4
Issue: 7-8
Pages: 247-260
DOI
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[Journal Article] Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas2013
Author(s)
Takeuchi, S. Wada, K. Toyooka, T. Shinomiya, N. Shimazaki, H. Nakanishi, K. Nagatani, K. Otani, N. Osada, H. Uozumi, Y. Matsuo, H. Nawashiro, H.
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Journal Title
Neurosurgery
Volume: 72(1)
Issue: 1
Pages: 33-41
DOI
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Peer Reviewed
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[Journal Article] A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility2013
Author(s)
Nakayama, A. Matsuo, H. Shimizu, T. Ogata, H. Takada, Y. Nakashima, H. Nakamura, T. Shimizu, S. Chiba, T. Sakiyama, M. Ushiyama, C. Takada, T. Inoue, K. Kawai, S. Hishida, A. Wakai, K. Hamajima, N. Ichida, K. Sakurai, Y. Kato, Y. Shimizu, T. Shinomiya, N.
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Journal Title
Hum Cell
Volume: 26(4)
Issue: 4
Pages: 133-6
DOI
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Peer Reviewed
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[Journal Article] Linezolid and vancomycin decrease the therapeutic effect of methylene blue-photodynamic therapy in a mouse model of MRSA bacterial arthritis2013
Author(s)
Tanaka, M. Mroz, P. Dai, T. Huang, L. Morimoto, Y. Kinoshita, M. Yoshihara, Y. Shinomiya, N. Seki, S. Nemoto, K. Hamblin, M. R.
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Journal Title
Photochem Photobiol
Volume: 89(3)
Issue: 3
Pages: 679-82
DOI
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Peer Reviewed
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[Journal Article] A new protocol to discover novel anti-aging compounds2012
Author(s)
F. Uchiumi, T. Oyama, K. Ozaki, M. Fukui, H. Ogawa, Y. Sasaki, H. Tachibana, C. Fukushima, M. Fujikawa, H. Abe, S. Larsen, S. Tanuma
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Journal Title
Pharmaceutica Analytica Acta
Volume: 3
Issue: 07
Pages: 166-166
DOI
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Peer Reviewed
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[Journal Article] Novel Compound SK-1009 Suppresses Interleukin-6 Expression through Modulation of Activation of Nuclear Factor-KappaB Pathway2012
Author(s)
Shimura, M., Yamamoto, M., Fujii, G., Takahashi, M., Komiya, M., Noma, N., Tanuma, S., Yanaka, A., Mutoh, M.
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Journal Title
Biological and Pharmaceutical Bulletin
Volume: 35
Issue: 12
Pages: 2186-2191
DOI
NAID
ISSN
0918-6158, 1347-5215
Related Report
Peer Reviewed
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[Journal Article] Cancer susceptibility polymorphism of p53 at codon 72 affects phosphorylation and degradation of p53 protein2011
Author(s)
Ozeki C., Sawai Y., Shibata T., Kohno T., Okamoto K., Yokota J., Tashiro F., Tanuma S., Sakai R., Kawase T., Kitabayashi I., Taya Y., and Ohki R
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Journal Title
J Biol Chem
Volume: 286(20)
Issue: 20
Pages: 18251-60
DOI
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[Journal Article] Airport quarantine inspection, follow-up observation, and the prevention of pandemic influenza2011
Author(s)
Fujita, M., Sato, H., Kaku, K., Tokuno, S., Kanatani, Y., Suzuki, S., Shinomiya, N.
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Journal Title
Aviat Space Environ Med
Volume: 82
Issue: 8
Pages: 782-789
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Peer Reviewed
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[Journal Article] Enhancement of Neutrophil Function by Interleukin-18 Therapy Protects Burn-Injured Mice from Methicillin-Resistant Staphylococcus aureus2011
Author(s)
Kinoshita, M., Miyazaki, H., Ono, S., Inatsu, A., Nakashima, H., Tsujimoto, H., Shinomiya, N., Saitoh, D., Seki, S.
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Journal Title
Infect Immun
Volume: 79
Issue: 7
Pages: 2670-2680
DOI
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Peer Reviewed
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[Journal Article] Identification of ABCG2 dysfunction as a major factor contributing to gout2011
Author(s)
H.Matsuo, T.Takada, K.Ichida, T.Nakamura, A.Nakayama, Y.Takada, C.Okada, Y.Sakurai, T.Hosoya, Y.Kanai, H.Suzuki, N.Shinomiya
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Journal Title
Nucleosides Nucleotides Nucleic Acids
Volume: 30
Issue: 12
Pages: 1098-1104
DOI
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Peer Reviewed
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[Journal Article] The immunologic outcome of enhanced function of mouse liver lymphocytes and Kupffer cells by high-fat and high-cholesterol diet2011
Author(s)
Shono, S., Habu, Y, Nakashima, M., Sato, A., Nakashima, H., Miyazaki, H., Kinoshita, M., Tsumatori, G., Shinomiya, N., Seki, S.
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Journal Title
Shock
Volume: 36
Issue: 5
Pages: 484-493
DOI
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Peer Reviewed
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[Journal Article] Photodynamic therapy using intra-articular Photofrin for murine MRSA arthritis : biphasic light dose response for neutrophil-mediated antibacterial effect2011
Author(s)
Tanaka, M., Kinoshita, M., Yoshihara, Y., Shinomiya, N., Seki, S., Nemoto, K., Hamblin, M.R., Morimoto, Y.
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Journal Title
Lasers Surg Med
Volume: 43
Issue: 3
Pages: 221-229
DOI
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Peer Reviewed
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[Presentation] Dysfunctional ABCG2 by common variants is a major cause of early-onset gout2014
Author(s)
Matsuo H, Ichida K, Takada T, Nakayama A, Nakashima H, Nakamura T, Takada Y, Shimizu S, Sakiyama M, Chiba T, Hamajima N, Sakurai Y, Shinomiya N
Organizer
5th FEBS Special Meeting on ABC Proteins
Place of Presentation
Innsbruck, Austria
Related Report
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[Presentation] ABCG2 SNP typing by Quenching-Probe method: Effective approach for gout and hyperuricemia risk evaluation2014
Author(s)
Sakiyama M, Matsuo H, Takada Y, Nakayama A, Shimizu S, Chiba T, Tatsukawa S, Shichijo Y, Nakashima H, Shimizu T, Sakurai Y, Shinomiya N
Organizer
5th FEBS Special Meeting on ABC Proteins
Place of Presentation
Innsbruck, Austria
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[Presentation] 痛風病因遺伝子ABCG2の変異と血清尿酸値との関連2012
Author(s)
中山昌喜, 松尾洋孝, 及川雄二, 高田雄三, 中島宏, 中村好宏, 井上寛規, 森厚嘉, 内藤真理子, 菱田朝陽, 若井建志, 丹羽和紀, 横井裕, 浜島信之, 四ノ宮成祥
Organizer
第22回日本疫学会学術総会
Place of Presentation
東京
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