| Project/Area Number |
16H03293
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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 |
Chemical biology
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| Research Institution | Yokohama City University |
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Principal Investigator |
Ogata Kazuhiro 横浜市立大学, 医学研究科, 教授 (90260330)
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| Co-Investigator(Kenkyū-buntansha) |
浜田 恵輔 横浜市立大学, 医学部, 助教 (00344052)
仙石 徹 横浜市立大学, 医学部, 講師 (60576312)
椎名 政昭 横浜市立大学, 医学部, 助教 (30347299)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2016: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
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| Keywords | 転写因子 / 転写制御 / がん / 創薬 / 癌 / 医薬品探索 / 分子標的薬 |
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| Outline of Final Research Achievements |
The molecule targeted therapy has been shown to be effective against various cancers. One of the potential targets is a transcription factor because its mutation is known to be frequently involved in cancer development. However, few drugs targeting transcription factors have been available. We have aimed to develop anti-leukemic drugs targeting a transcription factor, Runx1. Runx1 is a master regulator of the blood cell development, and various mutations of Runx1 gene have frequently been found in acute myelogenous leukemia (AML) patients.
We have searched for compounds that could destabilize the regulatory region of Runx1-DNA binding based on the molecular structure, and verified that some compounds have an ability to bind to Runx1 and inhibit DNA binding of Runx1. Furthermore, we have shown that these compounds could inhibit the transcriptional activation ability of Runx1 and decrease the cell-survival rate for the Kasumi-1 AML cells with the Runx1 mutation.
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| Academic Significance and Societal Importance of the Research Achievements |
変異型の転写因子は、ドミナント・ネガティブな様式で転写制御異常を誘起し、細胞の分化異常やがん化の原因となり得る。そのため、変異分子を含んだ異常な複合体の形成要因となる分子間相互作用を標的とした阻害薬は有望な治療薬候補となる。我々は急性骨髄性白血病の発症に関わる主要な転写因子の一つであるRunx1のDNA結合活性における制御部位を分子構造解析と機能解析の結果から明らかにし、その領域を介してアロステリックな様式で作用し得るDNA結合阻害薬を複数見出した。今後、これら阻害薬の構造の最適化を目指す。これまでに転写因子を標的とした阻害薬の報告例は極めて少ないため、大きな波及効果を生むことを期待している。
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