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

2010 Fiscal Year Final Research 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 東京薬科大学, 薬学部, 教授 (10322562)
• Co-Investigator(Kenkyū-buntansha): YAMAZAKI Yuri (70459725)
• 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

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.

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 Volume: 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 Volume: 18 Pages: 3169-3174
  • Peer Reviewed
• [Journal Article] Acid catalyzed mono-dehydro-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: Tetra-hedron Volume: 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 Volume: 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: Chem Bio Chem Volume: 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
  • 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
  • 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
  • Year and Date: 2009-11-09
• [Presentation] Cyclic dipeptide-based microtu-bule depolymerization agents as vascular targeting anti-cancer drugs (2009)
  • Author(s): Y. Hayashi
  • Organizer: 7th AFMC Inter-national Medicinal Chemistry Congress
  • Place of Presentation: Cairns, Australia
  • 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
  • Year and Date: 2008-05-16
• [Remarks]
  • URL: http://www.ps.toyaku.ac.jp/wp/yakuhinkagaku/
• [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
  • Overseas
• [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
  • Overseas
• [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 Pharmaceuticals
  • Industrial Property Number: 特許権、US20080221122
  • Filing Date: 2008-09-11
  • Overseas