Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents
Project/Area Number |
20390036
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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 |
Drug development chemistry
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Research Institution | Tokyo University of Pharmacy and Life Science |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Yuri 東京薬科大学, 薬学部, 助手 (70459725)
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Project Period (FY) |
2008 – 2010
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Project Status |
Completed (Fiscal Year 2010)
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Budget Amount *help |
¥15,340,000 (Direct Cost: ¥11,800,000、Indirect Cost: ¥3,540,000)
Fiscal Year 2010: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2008: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
|
Keywords | 医薬品開発 / 抗がん剤 / 有機合成化学 / チューブリン作用薬 / プロドラッグ / ケミカルバイオロジー / 化学薬剤学 / 化学プローブ / 薬学 / 抗がん剤癌 / 血管内皮細胞障害 / チューブリン |
Research Abstract |
Our efforts to develop novel m icrotubule depolymerization agents, which was focused on a natural diketopiperazine, phenylahistin, have succeeded in creating a highly potent anticancer drug candidate "Plinabulin" in Phase II clinical trials as a "vascular disrupting agent", which induces tumor-selective vascular collapse. SAR study from plinabulin has been conducted to develop more potent derivatives. A benzophenone derivative KPU-133 exhibited a 30-times higher cytotoxicity than plinabulin and would be promising candidates for further drug development. Moreover, to improve the low water-solubility of plinabulin(<0.1 mg/mL), a highly water-soluble prodrug(6 mg/mL in water) was developed to regenerate the parent drug by a unique skeletal transformation from monolactim to DKP. On the other hand, investigation of the tubulin-binding site using chemical probes indicated that plinabulin derivatives could interact in the interfacial region of α-and β-tubulin, which partially overlaps with the colchicine-binding site.
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Report
(5 results)
Research Products
(64 results)
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[Journal Article] Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a bitin tag at the oxazole2011
Author(s)
Yamazaki, Y., Kido, Y., Hidaka, K., Yasui, H., Kiso, Y., Yakushiji, F., Hayashi, Y.
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Journal Title
Bioorg. Med. Chem
Volume: 19
Pages: 595-602
Related Report
Peer Reviewed
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[Journal Article] Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a bitin tag at the oxazole.2011
Author(s)
Yamazaki, Y., Kido, Y., Hidaka, K., Yasui, H., Kiso, Y., Yakushiji, F., Hayashi, Y.
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Journal Title
Bioorg.Med.Chem. 19
Pages: 595-602
Related Report
Peer Reviewed
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[Journal Article] Anti-microtubule "plinabulin" chemical probe KPU-244-B3 labeled both a-and b-tubulin2010
Author(s)
Yamazaki, Y., Sumikura, M., Hidaka, K., Yasui, H., Kiso, Y., Yakushiji, F., Hayashi, Y.
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Journal Title
Bioorg. Med. Chem
Volume: 18
Pages: 3169-3174
Related Report
Peer Reviewed
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[Journal Article] Anti-microtubule "plinabulin" chemical probe KPU-244-B3 labeled both a-and b-tubulin.2010
Author(s)
Yamazaki, Y., Sumikura, M., Hidaka, K., Yasui, H., Kiso, Y., Yakushiji, F., Hayashi, Y.
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Journal Title
Bioorg.Med.Chem. 18
Pages: 3169-3174
Related Report
Peer Reviewed
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[Journal Article] Acid catalyzed mono-dehydro-2, 5-diketopiperazine formation from N-α-ketoacyl amino acid amides2009
Author(s)
Yamazaki, Y., Mori, Y., Oda, A., Okuno, Y., Kiso, Y., Hayashi, Y.
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Journal Title
Tetra-hedron
Volume: 65
Pages: 3688-3694
Related Report
Peer Reviewed
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[Journal Article] Acid catalyzed monodehydro-2, 5-diketopiperazine formation from N-α-ketoacyl amino acid amides.2009
Author(s)
Yamazaki, Y., Mori, Y., Oda, A., Okuno, Y., Kiso, Y., Hayashi, Y.
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Journal Title
Tetrahedron 65
Pages: 3688-3694
Related Report
Peer Reviewed
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[Journal Article] Acid catalyzed monodehydro-2,5-diketopiperazine formation from N-α-ketoacyl amino acid amides2009
Author(s)
Yamazaki, Y., Mori, Y., Oda, A., Okuno.Y., Kiso, Y., Havashi, Y.
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Journal Title
Tetrahedron 65
Pages: 3688-3694
Related Report
Peer Reviewed
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[Journal Article] Acid catalyzed monodehydro-2,5-diketopiperazine formation toward natural product synthesis2009
Author(s)
Yamazaki, Y., Mori, Y., Oda, A., Kiso, Y., Hayashi, Y.
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Journal Title
Peptides 2009
Pages: 54-55
Related Report
Peer Reviewed
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[Journal Article] Synthesis and structure-activity relationship study of cyclic dipeptide-based microtubule depolymerization agents with a benzophenone structure2009
Author(s)
Sumikura, M., Yamazaki, Y., Yoshida, T., Mori, Y., Yasui, H., Kiso, Y., Neuteboom, S., Potts, B., Lloyd, G.K., Hayashi, Y.
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Journal Title
Peptide Science 2009 2009(in press)
Pages: 315-316
Related Report
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[Journal Article] Oligoarginine-based prodrugs with self-cleavable spacers for Caco-2 cell permeation2008
Author(s)
Takayama, K., Suehisa, Y., Fujita, T., Nguyen, J-T., Futaki, S., Yamamoto, A., Kiso, Y., Hayashi, Y.
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Journal Title
Chem. Pharm. Bull
Volume: 56
Pages: 1515-1520
NAID
Related Report
Peer Reviewed
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[Journal Article] Tubulin Photoaffinity Labeling by Biotin-Tagged Derivatives of Potent Diketopiperazine Anti-Microtubule Agents2008
Author(s)
Yamazaki, Y., Kohno, K., Yasui, H., Kiso, Y., Akamatsu, M., Nicholson, B., Deyanat-Yazdi, G., Neuteboom, S., Potts, B., Lloyd, G. K., Hayashi, Y.
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Journal Title
Chem Bio Chem
Volume: 9
Pages: 3074-3081
Related Report
Peer Reviewed
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[Journal Article] Oligoarginine-based prodrugs with self-cleavable spacers for Caco-2 cell permeation.2008
Author(s)
Takayama, K., Suehisa, Y., Fujita, T., Nguyen, J-T., Futaki, S., Yamamoto, A., Kiso, Y., Hayashi, Y.
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Journal Title
Chem.Pharm.Bull. 56
Pages: 1515-1520
NAID
Related Report
Peer Reviewed
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[Journal Article] Tubulin Photoaffinity Labeling by Biotin-Tagged Derivatives of Potent Diketopiperazine Anti-Microtubule Agents.2008
Author(s)
Yamazaki, Y., Kohno, K., Yasui, H., Kiso, Y., Akamatsu, M., Nicholson, B., Deyanat-Yazdi, G., Neuteboom, S., Potts, B., Lloyd, G.K., Hayashi, Y.
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Journal Title
ChemBioChem 9
Pages: 3074-3081
Related Report
Peer Reviewed
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[Presentation] "Plinabulin" a diketopiperazine-type vascular targeting anti-cancer agent based on microtubule depolymerization activity2010
Author(s)
Hayashi, Y., Yamazaki, Y., Sumikura, M., Yoshida, T., Mori, Y., Yasui, H., Kohno, K., Kiso, Y., Neuteboom, S., Potts, B., Lloyd, G.K.
Organizer
ACS Spring 2010 National Meeting & Exposition
Place of Presentation
San Francisco, USA
Year and Date
2010-03-21
Related Report
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[Presentation] "Plinabulin" a cyclic dipeptide-based vascular targeting anti-cancer agent based on microtubule depolymerization activity2009
Author(s)
Hayashi, Y., Yamazaki, Y., Sumikura, M., Yoshida, T., Mori, Y., Yasui, H., Kohno, K., Kiso, Y., Neuteboom, S., Potts, B., Lloyd, G.K.
Organizer
3rd Asia-Pacific International Peptide Symposium / 13th Korean Peptide and Protein Symposium
Place of Presentation
Jeju Island, Korea
Year and Date
2009-11-08
Related Report
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[Presentation] Synthesis and structure-activity relationship study of cyclic dipeptide-based microtubule depolymerization agents with a benzophenone structure2009
Author(s)
Sumikura, M., Yamazaki, Y., Yoshida, T., Mori, Y., Yasui, H., Kiso, Y., Neuteboom, S., Potts, B., Lloyd, G.K., Hayashi, Y.
Organizer
46th Japanese Peptide Symposium
Place of Presentation
Kitakyushu, Japan
Year and Date
2009-11-04
Related Report
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[Presentation] Cyclic dipeptide-based microtubule depolymerization agents as vascular targeting anti-cancer drugs2009
Author(s)
Yamazaki, Y., Sumikura, M., Yoshida, T., Mori, Y., Yasui, H., Kohno, K., Kiso, Y., Deyanat-Yazdi, G., Neuteboom, S., Potts, B., Lloyd, G.K., Hayashi, Y.
Organizer
7th AFMC International Medicinal Chemistry Congress
Place of Presentation
Cairns, Australia
Year and Date
2009-08-23
Related Report
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[Presentation] Acid catalyzed monodehydro-2,5-diketopiperazine formation toward natural product synthesis2009
Author(s)
Yamazaki, Y., Mori, Y., Oda, A., Kiso, Y., Hayashi, Y.
Organizer
21st American Peptide Symposium
Place of Presentation
Bloomington, IN, USA
Year and Date
2009-06-07
Related Report
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