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Development of new agents that regulate cellular signal transduction

Research Project

Project/Area Number 15208012
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioproduction chemistry/Bioorganic chemistry
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

OHIGASHI Hajime  Kyoto Univ., Grad.Sch.Agric., Professor, 農学研究科, 教授 (80026583)

Co-Investigator(Kenkyū-buntansha) IRIE Kazuhiro  Kyoto Univ., Grad.Sch.Sci., Associate Professor, 農学研究科, 助教授 (00168535)
SAITO Naoaki  Kobe Univ., Biosignal Research Center, Professor, バイオシグナル研究センター, 教授 (60178499)
Project Period (FY) 2003 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥44,460,000 (Direct Cost: ¥34,200,000、Indirect Cost: ¥10,260,000)
Fiscal Year 2006: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2005: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
Fiscal Year 2004: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2003: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Keywordsaplysiatoxin / bryostatin / C1 domain / diacylglycerol kinase / indolactam / phorbol ester / protein kinase C / tumor promoter / 亜鉛フィンガー / C1ドメイン / プロテインキナーゼC / GFP / RasGRP / chimaerin / Unc13 / indolactam-V
Research Abstract

Protein kinase C (PKC) isozymes are major receptors of tumor-promoting phorbol esters. They contain two cysteine-rich C1 domains (C1A, C1B), both of which are candidates for phorbol 12,13-dibutyrate (PDBu) binding sites. To investigate the mechanism of tumor promotion in molecular level, the C1 peptides corresponding to the C1 domains of all PKC isozymes were synthesized, and their dissociation constants for PDBu were measured. The resultant C1 peptide library was used to screen for new ligands with PKC isozyme and C1 domain selectivity to find that indolactam-V (IL-V) is a promising lead compound.
We verified that the indole ring of IL-V could be involved in the CH/πinteraction with Pro-11 of the C1B domain of PKCδ using its mutant peptide, in which the CH/π interaction was inhibited by substitution of the hydrogen atom with a fluorine atom at position 4 of Pro-11. IL-V showed about a 10 times lower binding affinity to the mutant peptide compared to the wild-type peptide, suggesting th … More at the CH/π interaction could play a pivotal role on the binding of IL-V to the PKCδ C1B domain. On the other hand, benzolactam-V8 (BL-V8), with the benzene ring instead of the indole ring of IL-V, might lack the CH/π interaction. The low binding affinity of BL-V8 could be enhanced by the effective formation of the CH/n interaction as exemplified by the synthesis of naphtholactam-V8. Based on the difference among the CH/π interaction in PKC isozymes, 1-hexyl-indolactma-V10 and 8-octyl-benzolactam-V9 with potent selectivity for novel PKC isozymes (δ,ε,η,θ) that play significant roles in tumor promotion were developed. Moreover, a simplified analogue of tumor-promoting aplysiatoxin with less hydrophobicity was design-synthesized and shown to translocate PKCδ from cytosol to nuclear membrane like bryostatin 1 with anti-neoplastic activity.
Recently, new phorbol ester receptors other than PKC (n-chimaerins, Unc-13s, and RasGRPs) have been reported. We unambiguously demonstrated that diacylglycerol kinase (DGK) γ and β are new targets of tumor-promoting phorbol esters by synthesizing the C1 peptides of all DGK isozymes. Less

Report

(5 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (31 results)

All 2006 2005 2004 2003 Other

All Journal Article (29 results) Publications (2 results)

  • [Journal Article] CH/π 相互作用を利用した薬剤開発2006

    • Author(s)
      入江 一浩
    • Journal Title

      ファルマシア 42・5

      Pages: 427-430

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Design and synthesis of 8-octyl-benzolactam-V9, the selective activator for PKCε and η2006

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Journal of Medicinal Chemistry 49・9

      Pages: 2681-2688

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Development of new medicinal leads based on the CH/π interaction.2006

    • Author(s)
      K.Irie
    • Journal Title

      Pharmacia 42 (5)

      Pages: 427-430

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Design and synthesis of 8-octyl-benzolactam-V9, the selective activator for PKCε and η.2006

    • Author(s)
      Y.Nakagawa, K.Irie, R.C.Yanagita, H.Ohigashi, K.-i.Tsuda, K.Kashiwagi, N.Saito
    • Journal Title

      J. Med. Chem. 49 (9)

      Pages: 2681-2688

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase Cε and η2006

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Journal of Medicinal Chemistry 49・9

      Pages: 2681-2688

    • Related Report
      2006 Annual Research Report
  • [Journal Article] CH/π相互作用を利用した薬剤開発2006

    • Author(s)
      入江 一浩
    • Journal Title

      ファルマシア 42・5

      Pages: 427-430

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Design and synthesis of 8-octyl-benzolactam-V9,a selective activator for protein kinase Cε and η2006

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Journal of Medicinal Chemistry (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Toward the development of new medicinal leads with selectivity for protein kinase C isozymes2005

    • Author(s)
      Kazuhiro Irie
    • Journal Title

      The Chemical Record 5・4

      Pages: 185-195

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Indolactam-V is involved in the CH/π interaction with Pro-11 of the PKCδ C1B domain : application for the structural optimization of the PKCδ ligand2005

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Journal of the American Chemical Society 127・16

      Pages: 5746-5747

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Indolactam-V is involved in the CH/π interaction with Pro-11 of the PKCδ C1B domain : application for the structural optimization of the PKCδ ligand.2005

    • Author(s)
      Y.Nakagawa, K.Irie, R.C Yanagita, H.Ohigashi, K.-i.Tsuda
    • Journal Title

      J. Am. Chem. Soc. 127 (16)

      Pages: 5746-5747

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Toward the development of new medicinal leads with selectivity for protein kinase C isozymes.2005

    • Author(s)
      K.Irie, Y.Nakagawa, H.Ohigashi
    • Journal Title

      Chem. Rec. 5 (4)

      Pages: 185-195

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Indolactam-V is involved in the CH/π interaction with Pro-11 of the PKCδ domain : application for the structural optimization of the PKCδ ligand2005

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Journal of the American Chemical Society 127・16

      Pages: 5746-5747

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Indolactam and benzolactam compounds as new medicinal leads with binding selectivity for C1 domains of protein kinase C isozymes2004

    • Author(s)
      Kazuhiro Irie
    • Journal Title

      Current Pharmaceutical Design 10・12

      Pages: 1371-1385

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] ペプチド合成によるホルボールエステル受容体の機能解析2004

    • Author(s)
      入江 一浩
    • Journal Title

      化学と生物 42・1

      Pages: 54-62

    • NAID

      10012135570

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally-restricted analogues of (-)-indolactam-V2004

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Tetrahedron 60・33

      Pages: 7077-7084

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Tumor promoter binding of the protein kinse C C1 homology domain peptides of RasGRPs, chimaerins, and Unc13s2004

    • Author(s)
      Kazuhiro Irie
    • Journal Title

      Bioorganic & Medicinal Chemistry 12・7

      Pages: 4575-4583

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally-restricted analogues of (-)-indolactam-V.2004

    • Author(s)
      Y.Nakagawa, K.Irie, Y.Komiya, H.Ohigashi, K.-i.Tsuda
    • Journal Title

      Tetrahedron 60 (33)

      Pages: 7077-7084

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Indolactam and benzolactam compounds as new medicinal leads with binding selectivity for C1 domains of protein kinase C isozymes.2004

    • Author(s)
      K.Irie, Y.Nakagawa, H.Ohigashi
    • Journal Title

      Curr. Pharm. Design 10 (12)

      Pages: 1371-1385

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Tumor promoter binding of the protein kinase C C1 homology domain peptides of RasGRPs, chimaerins, and Unc13s.2004

    • Author(s)
      K.Irie, A.Masuda, M.Shindo, Y.Nakagawa, H.Ohigashi
    • Journal Title

      Bioorg. Med. Chem. 12 (17)

      Pages: 4575-4583

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Functional analysis of the phorbol ester receptors using a peptide synthesis.2004

    • Author(s)
      K.Irie, H.Ohigashi
    • Journal Title

      Kagaku to Seibutsu 42 (1)

      Pages: 54-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Indolactam and Benzolactam Compounds as New Medicinal Leads with Binding Selectivity for C1 Domains of Protein Kinase C Isozymes2004

    • Author(s)
      Kazuhiro Irie
    • Journal Title

      Current Pharmaceutical Design 10・12

      Pages: 1371-1385

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Tumor promoter binding of the protein kinase C C1 homology domain peptides of RasGRPs, chimaerins, and Unc13s2004

    • Author(s)
      Kazuhiro Irie
    • Journal Title

      Bioorganic & Medicinal Chemistry 12・17

      Pages: 4575-4583

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synthesis, conformation and PKC isozyme surrogate binding of indolinelactam-Vs, new conformationally restricted analogues of (-)-indolactam-V2004

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Tetrahedron 60・33

      Pages: 7077-7084

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Analysis of the non-covalent interaction between metal ions and the cysteine-rich domain of protein kinase C eta by electrospray ionization mass spectrometry2003

    • Author(s)
      Mayumi Shindo
    • Journal Title

      Bioorganic & Medicinal Chemistry 11・23

      Pages: 5075-5082

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis and binding selectivity of 7- and 15-decylbenzolactone-V8 for the C1 domains of protein kinase C isozymes2003

    • Author(s)
      Yu Nakagawa
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters 13・18

      Pages: 3015-3019

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis and phorbol ester binding of the cysteine-rich domains of diacylglycerol kinase (DGK) isozymes : DGKγ and DGKβ are new targets of tumor-promotins phorbol esters2003

    • Author(s)
      Mayumi Shindo
    • Journal Title

      The Journal of Biological Chemistry 278・20

      Pages: 18448-18454

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis and phorbol ester binding of the cysteine-rich domains of diacylglycerol kinase (DGK) isozymes; DGKγ and DGKβ are new targets of tumor-promoting phorbol esters.2003

    • Author(s)
      M.Shindo, K.Irie, A.Masuda, H.Ohigashi, Y.Shirai, K.Miyasaka, N.Saito
    • Journal Title

      J. Biol. Chem. 278 (20)

      Pages: 18448-18454

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis and binding selectivity of 7-and 15-decylbenzolactone-V8 for the C1 domains of protein kinase C isozymes.2003

    • Author(s)
      Y.Nakagawa, K.Irie, N.Yamanaka, H.Ohigashi, K.-i.Tsuda
    • Journal Title

      Bioorg. Med. Chem. Lett. 13 (18)

      Pages: 3015-3019

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Analysis of the non-covalent interaction beween metal ions and the cysteine-rich domain of protein kinase C eta by electrospray ionization mass spectrometry.2003

    • Author(s)
      M.Shindo, K.Irie, H.Fukuda, H.Ohigashi
    • Journal Title

      Bioorg. Med. Chem. 11 (23)

      Pages: 5075-5082

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Publications] Mayumi Shindo: "Synthesis and phorbol ester binding of the cysteine-rich domains of diacylglycerol kinase(DGK) isozymes"The Journal of Biological Chemistry. 278・20. 18448-18454 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 入江 一浩: "ペプチド合成によるホルボールエステル受容体の機能解析"化学と生物. 42・1. 54-62 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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