Design of the anti-tumor agents targeting the functional proteins involved in cancer cell growth
| Project/Area Number |
15310154
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Living organism molecular science
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| Research Institution | Kansai University |
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Principal Investigator |
UESATO Shinichi Kansai University, Faculty of engineering, professor, 工学部, 教授 (50111969)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAOKA Yasuo Kansai University, Faculty of engineering, associate professor, 工学部, 助教授 (90243039)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2003: ¥7,300,000 (Direct Cost: ¥7,300,000)
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| Keywords | histone deacetylase / P388 / p21 / WAF1 / human normal fibroblast cell / Her2 / neu / SKBR3 / o-aminothiophenol / Herceptin / ヒト正常繊維芽細胞 / フッ素原子 / 血漿中安定性試験 / o-アミノチオフェノール誘導体 / Her2高発現型乳癌細胞 / ハーセプチン / ヒストン脱アセチル化酵素阻害剤 / P388担癌マウス実験 / HCT116 / SK-BR-3 / 細胞周期停止 / Her2高発現型乳がん細胞 / 緑茶カテキン / Her / HT-29 / SW620 / (-)-epigallocatechin gallate / (-)-epigallocatechin / 抗がん剤 |
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| Research Abstract |
Design of new histone deacetylase (HDAC) inhibitors
We succeeded in the synthesis of 6-amino-2-naphthyl-containing HDAC inhibitor K-32 which exhibited a marked survival effect (%T/C, 185) in the P388 cell-inoculated mice experiment. It was found out that the inhibitory effect on cancer cell proliferation by K-32 involves p21/WAF1 induction and G2/M phase arrest. Among the 2-aminobenzyl-type HDAC inhibitors, K-198 possessing a 3,4-difluorobenzyl group was less toxic to the normal fibroblast cell than SAHA and MS-275 under clinical stages. Furthermore, K-197 comprising a 1,3-benzodioxol group showed more or less the same toxicity as did SAHA. These two compounds exhibited a high recovery in human plasma stability test. Further study on K-32, K-197 and K-198 is underway to investigate the therapeutic efficacy against human cancers.
Design of new low-molecular inhibitors bound to the Her2/neu protein
We demonstrated that green catechins : (-)-epigallocatechin and (-)-epigallocatechin gallate inhibited the cell growth of Her2/neu-overexpressing SKBR3. These catechins seem to suppress the cell growth through inhibition of Her2 dimerization and/or its phosphorylation. Additionally, we discovered the o-aminothiophenol derivative K-154 as an SKBR3 antiprolierative compound ; this compound might have displayed an efficacy through a S-S bond formation between the SH of K-154 and a cysteine of Her2 protein. Thus, K-154 can be a lead compound to seek a cancer therapeutic agent acting as substitute for Herceptin.
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Report
(4 results)
Research Products
(34 results)
