Clarification research for molecular mechanism of a novel type of protein kinase C inhibitor

新型蛋白激酶C抑制剂分子机制的阐明研究

• 批准号: 21603016
• 负责人: SODEOKA Mikiko
• 金额: $ 2.83万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21603016/
• 关键词: プロテインキナーゼC; 酵素阻害剤; Isobenzofuranone誘導体; ホスファチジルセリン; 構造活性相関; 有機合成; Phosphatidylserine; ホルボールエステル

In this research grant, we intended to clarify the activation mechanism of protein kinase C(PKC) at molecular level by utilizing isobenzofuranone(IB) derivatives, which were designed based on the physiological activators, diacylglycerols(DAG), for PKC. IB derivatives showed either activation or inhibition of PKC・depended on their substituents. Although the main subject of this research was clarification of the inhibition mechanism of PKC inhibitor IB-15A, analysis of the PKC activators was also necessary. In these three years, we first revealed the features of several PKC activators. And then we found that a potent PKC inhibitor IB-15A showed inhibition of PKC・by probably through the distinct binding site from that of the typical PKC activator and by disturbing the interaction of PKC with lipid.

本研究以蛋白激酶C（PKC）的生理激活剂二酰基甘油（diacylglycerols，DAG）为基础，设计了异苯并呋喃酮（isobenzofuranone，IB）衍生物，旨在从分子水平阐明PKC的激活机制。IB衍生物对PKC·的激活或抑制作用依赖于取代基。虽然本研究的主要目的是阐明PKC抑制剂IB-15 A的抑制机制，但对PKC激活剂的分析也是必要的。在这三年中，我们首次揭示了几种PKC激活剂的特性。研究发现，一种强有力的PKC抑制剂IB-15 A可能通过与典型的PKC激活剂不同的结合位点以及干扰PKC与脂质的相互作用而抑制PKC·。

项目成果

新規Isobenzofuranone誘導体のPKC阻害活性と作用機序に関する研究

新型异苯并呋喃酮衍生物PKC抑制活性及作用机制研究

• 发表时间: 2009
• 作者: 田村結城;平井剛;大窪恵;袖岡幹子
• 通讯作者: 袖岡幹子

Design and synthesis of protein kinase Cαactivators based on .'out of pocket' interactions

基于“自掏腰包”相互作用的蛋白激酶 Cα 激活剂的设计和合成

• 发表时间: 2011
• 期刊: Bioorg. Med. Chem. Lett
• 作者: Hirai;G.;Ohkubo;M.;Tamura;Y. and Sodeoka;M.
• 通讯作者: M.

Novel isobenzofuranone derivatives having Protein Kinase C inhibitory activity

具有蛋白激酶C抑制活性的新型异苯并呋喃酮衍生物

• 发表时间: 2010
• 作者: Tamura;Y.;et al;Yuki Tamura
• 通讯作者: Yuki Tamura

Study on PKC inhibition by novel isobenzofuranone derivatives and their mechanism of action

新型异苯并呋喃酮衍生物抑制PKC及其作用机制研究

• 发表时间: 2009
• 作者: Yuki Tamura;Go Hirai;Megumi Ohkubo;Mikiko Sodeoka
• 通讯作者: Mikiko Sodeoka

天然物や生体分子を基盤とした生理活性分子の創製

基于天然产物和生物分子创建生物活性分子

• 发表时间: 2010
• 作者: Tadashi Kimura;Seigo Ono and Tai Kubo;平井剛;森田昌樹;小沢正晃;森田昌樹;森田昌樹;Go Hirai;森田昌樹;平井剛
• 通讯作者: 平井剛