Development and mechanistic analysis of new PKC ligands as anti-cancer agents

2015 Fiscal Year Final Research Report

• Project Area: Chemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity
• Project/Area Number: 23102011
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Kyoto University
• Principal Investigator: IRIE Kazuhiro 京都大学, (連合)農学研究科(研究院), 教授 (00168535)
• Co-Investigator(Kenkyū-buntansha): YANAGITA Ryo C. 香川大学, 農学部, 助教 (10598121)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: アプリシアトキシン / アプログ / ブリオスタチン / がん細胞増殖抑制 / プロテインキナーゼＣ / ホルボールエステル / 発がんプロモーター

Outline of Final Research Achievements

Protein kinase C (PKC) isozymes play central roles in the signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer and Alzheimer's disease. Although natural PKC ligands like phorbol esters have the potential to become therapeutic leads, most of them are potent tumor promoters and proinflammatory on mouse skin. We focused on the skeleton of aplysiatoxin (ATX), a natural PKC ligand isolated from sea hare. We found 10-methyl-aplog-1, a simplified analog of ATX, to have strong anti-proliferative activity against several cancer cell lines with little tumor-promoting and inflammatory activities. In order to examine the anti-cancer activity in vivo and mechanism of action, several hundred milligrams of 10-methyl-aplog-1 was synthesized. 10-Methyl-aplog-1 exhibited significant anti-cancer activity against mouse xenograft models, and its anti-proliferative activity derived in part from activation of protein kinase C α.

Free Research Field

生物有機化学