Study on Medicinal Chemistry, Chemical Biology and Chemical Pharmaceutics of Anticancer Drug Based on the Microtubule Targeting Agents

2010 Fiscal Year Self-evaluation Report

• Project/Area Number: 20390036
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: HAYASHI Yoshio Tokyo University of Pharmacy and Life Science, 薬学部, 教授 (10322562)
• Project Period (FY): 2008 – 2010
• 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

Research Abstract

本研究は,微小管作用に基づく腫瘍選択的新生血管内皮細胞障害剤の創薬研究を中核とし,分子機能を探るケミカルバイオロジー研究、さらに微小管作用薬の薬剤学的高度機能化研究を統合的に実施するもので,抗がん剤として重要な微小管作用薬の新しい潮流を総合的に開拓するものである。特に微小管脱重合作用を基盤に,新生血管内皮細胞障害剤(Vascular Disrupting Agent, VDA)の創薬研究である。
本申請者は天然物微小管脱重合物質フェニラヒスチン(PLH)を戦略分子とする創薬研究から強力なVDA(Plinabulin)の創製に既に成功している。当該物質は前臨床試験を経て、現在世界4カ国で第II相臨床試験が実施中であるが,本研究ではPlinabulinを基に第二世代のVDA型抗がん剤開発、水溶性プロドラッグ,腫瘍高選択性光応答型プロドラッグの創製研究、更にケミカルバイオロジーに応用可能な光標識プローブの開発を通じ,血管内皮細胞障害作用のメカニズム解明をめざす研究である。また、薬剤耐性発現など複数の薬剤学的課題を解決可能な化学薬剤学の展開を図るものである。高活性誘導体創製,水溶性プロドラッグへの変換や耐性を克服し経口投与を可能にする薬剤への分子進化は、有機合成化学を先導的に利用して展開する。すなわち、本申請の研究課題では,これらを統合的に研究・融合させることで,がん化学療法で重要な微小管作用薬の新しい潮流を構築する。

Research Products

• [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.
  • Journal Title: Bioorg.Med.Chem. 19 Pages: 595-602
  • Peer Reviewed
• [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.
  • Journal Title: Bioorg.Med.Chem. 18 Pages: 3169-3174
  • Peer Reviewed
• [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.
  • Journal Title: Tetrahedron 65 Pages: 3688-3694
  • Peer Reviewed
• [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.
  • Journal Title: Chem.Pharm.Bull. 56 Pages: 1515-1520
  • Peer Reviewed
• [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.
  • Journal Title: ChemBioChem 9 Pages: 3074-3081
  • Peer Reviewed
• [Presentation] Development of chemical probes towards the elucidation of binding mechanism of plinabulin, a cyclicdipeptide based anti-microtubule agent (2010)
  • Author(s): Yuri Yamazaki
  • Organizer: 5th International Peptide Symposium in conjunction with 47th Japanese Peptide Symposium
  • Place of Presentation: Kyoto(口頭発表)
  • Year and Date: 2010-12-04
• [Presentation] Plinabulin a diketopiperazine .type vascular targeting anti-cancer agent based on microtubule depolymerization activity (2010)
  • Author(s): Yoshio Hayashi
  • Organizer: ACS Spring 2010 National Meeting & Exposition
  • Place of Presentation: San Francisco, USA(招待後援)
  • Year and Date: 2010-03-22
• [Presentation] Plinabulin a cyclic dipeptide-based vascular targeting anti-cancer agent based on microtubule depolymerization activity (2009)
  • Author(s): Yoshio Hayashi
  • Organizer: 3rd Asia-Pacific International Peptide Symposium/13th Korean Peptide and Protein Symposium : "Peptides at Cutting Edge"
  • Place of Presentation: Jeju Island, Korea(口頭発表)
  • Year and Date: 2009-11-09
• [Presentation] Cyclic dipeptide-based microtubule depolymerization agents as vascular targeting anti-cancer drugs (2009)
  • Author(s): Y.Hayashi
  • Organizer: 7th AFMC International Medicinal Chemistry Congress
  • Place of Presentation: Cairns, Australia(口頭発表)
  • Year and Date: 2009-08-27
• [Presentation] A new microtubule targeting agent as a vascular targeting anti-cancer drug (2008)
  • Author(s): Yoshio Hayashi
  • Organizer: 12th Akabori Conference : German-Japanese Symposium on Peptide Science
  • Place of Presentation: Kyoto(口頭発表)
  • Year and Date: 2008-05-16
• [Patent(Industrial Property Rights)] Synthesis Of Diketopiperazines (2010)
  • Inventor(s): Yoshio Hayashi
  • Industrial Property Rights Holder: Nereus Pharmaceuticals
  • Industrial Property Number: 特許権,US7732605
  • Acquisition Date: 2010-06-08
• [Patent(Industrial Property Rights)] Dehydrophenylahistins And Analogs Thereof And The Synthesis Of Dehydrophenyla-histins And Analogs Thereof (2010)
  • Inventor(s): Yoshio Hayashi, Michael A Palladino Jr, Jennifer Grodberg
  • Industrial Property Rights Holder: Nereus Pharmaceuticals
  • Industrial Property Number: 特許権,US7674903
  • Acquisition Date: 2010-03-09
• [Patent(Industrial Property Rights)] Analogs of dehydrophenylahistins and their therapeutic use and preparation. (2008)
  • Inventor(s): Michael A.Palladino, G.Kenneth Lloyd., Yoshio Hayashi
  • Industrial Property Rights Holder: Nereus Pharmacuticals
  • Industrial Property Number: 特許権,US20080221122
  • Filing Date: 2008-09-11