| Project/Area Number |
16K08718
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Jichi Medical University |
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Principal Investigator |
Nakaya Takeo 自治医科大学, 医学部, 講師 (80512277)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | KLF5 / 蛋白間相互作用 / 大腸癌 / 癌分子創薬 / 天然変性蛋白 / 転写因子 / 心不全 / ミトコンドリア / 蛋白間相互作用阻害 / 蛋白間相互作用阻害薬 / 癌選択的抑制 / KLF5阻害薬 / 新規抗癌薬 / 腫瘍 / 新規癌治療開発 |
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| Outline of Final Research Achievements |
We found that KLF5 is essential for tumorigenesis from intestinal epithelial stem cells, and is a promising molecular target for cancer treatment. However, it has been difficult to develop inhibitors of KLF due to the lack of clarification of their 3D structure. We have developed new anticancer drugs, small molecule compounds that are expected to inhibit the protein-protein interactions of KLF5. The results showed that the compounds selectively suppressed human colon cancer cells without damaging normal human cell, and suppressed transplanted human colorectal cancer cell tumors in mice. The compounds suppressed the quantities of KLF5 and other proteins in cancer cells, but not in normal cells. We have discovered a structure-activity relationship between chemical structure and tumor cell suppression, and have created compounds with high tumor suppression potential. We identified the binding proteins of the compounds and elucidated the molecular mechanism of action.
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| Academic Significance and Societal Importance of the Research Achievements |
がんゲノム解析に基づきゲノム異常に応じた分子標的薬を用いるがんprecision medicineが求められている。しかし、がん原因因子の多くは、立体構造を解明できない天然変性蛋白であり、立体構造に基づく分子標的薬の開発が難しい。また、がん原因因子の多くは、低分子化合物でないと到達し作用できない核内因子である。このため、がん原因因子の多くに対し分子標的薬が開発されておらず、がんゲノム解析を行っても新たに有効な治療薬が見出される率は低いままである。本研究は、よい分子標的薬のなかった天然変性蛋白、核内因子に対しがん分子創薬を可能にし、進行がん患者の予後改善に貢献すると期待される。
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