Development of region-specific inhibitors against epigenomic aberrations critical for gastrointestinal tumorigenesis
Project/Area Number |
18K19572
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
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Research Institution | Chiba University |
Principal Investigator |
Kaneda Atsushi 千葉大学, 大学院医学研究院, 教授 (10313024)
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Project Period (FY) |
2018-06-29 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
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Keywords | 癌 / エピジェネティクス / 阻害剤 / PIポリアミド / エピゲノム / がん / 化合物合成 / ピロールイミダゾールポリアミド |
Outline of Final Research Achievements |
Taking advantage by utilizing small molecules that bind to DNA by sequence-specific manner, we develop middle molecule compounds that can rewrite the accumulated epigenomic aberrations or prevent their accumulations in targeted genomic regions. Pyrrole-imidazole (PI) polyamides are cell-permeable and intravenously injectable molecules with low toxicity that can bind to the minor groove of DNA by sequence-specific manner. Epigeneitic inhibitors are conjugated to PI polyamides, and delivered to the targeted genomic regions by sequence-specific manner when given to cultured cancer cells. We established PI polyamides conjugated with epigenetic inhibitors that altered epigenome at selected regions. We also identified critical aberrant epigenomic alterations that were seen in cancer e.g. gastric and prostate cancer and could be candidate regions targeted by these conjugates.
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Academic Significance and Societal Importance of the Research Achievements |
エピゲノムとは細胞のゲノムの修飾物のことで、どの遺伝子を使いどの遺伝子を使わないか、つまりは細胞の運命や振舞いを決定する働きを持ち、その異常は癌の重要な原因の1つとなる。しかし現状のエピゲノム阻害剤は、癌の原因となっている異常修飾領域だけでなく、正常な細胞に存在する重要な修飾も含めてゲノム全体で作用してしまうことで副作用が問題となる。本研究は、特定の塩基配列を含む選択的なゲノム領域のみエピゲノム阻害剤が作用することを可能にする化合物開発に挑戦し、技術的に成功するとともに、次の発展を目指し胃癌・前立腺癌などで重要なエピゲノム異常を標的とする化合物開発へと進行している。
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Report
(3 results)
Research Products
(20 results)
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[Journal Article] Synthsis of LSD1 Inhibitor-Pyrrole-Imidazole Polyamide Conjugates for Region-Specific Alterations of Histone Modification2019
Author(s)
Qin R, Takayanagi S, Kondo Y, Li J, Shiga N, Nakajima M, Shinohara K, Yoda N, Suzuki T, Kaneda A, and Nemoto T
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Journal Title
Heterocycles
Volume: -
Issue: 2
Pages: 891-905
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Region-specific alteration of histone modification by LSD1 inhibitor conjugated with pyrrole-imidazole polyamide2018
Author(s)
Alagarswamy K, Shinohara K, Takayanagi S, Fukuyo M, Okabe A, Rahmutulla B, Yoda N, Qin R, Shiga N, Sugiura M, Sato H, Kita K, Suzuki T, Nemoto T, Kaneda A
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Journal Title
Oncotarget
Volume: 9
Issue: 50
Pages: 29316-29335
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] LSD1 Inhibitor Conjugated with PI Polyamide Enhances Region Specific Activation of Genomic Regions.2018
Author(s)
Kokiladevi Alagarswamy, Ken-ichi Shinohara, Shihori Takayanagi, Masaki Fukuyo, Atsushi Okabe, Bahityar Rahmutulla, Natsumi Yoda, Rui Qin, Naoki Shiga, Kazuko Kita, Takayoshi Suzuki, Tetsuhiro Nemoto, Atsushi Kaneda.
Organizer
Vanderbilt-Ingram Cancer Center Annual Scientific Retreat
Related Report
Int'l Joint Research
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[Presentation] DNA結合小分子を応用した領域選択的エピゲノム制御概念の開発.2018
Author(s)
篠原憲一, 依田夏美, 福世真樹, 岡部篤史, Kokiladevi Alagarswamy, Bahityar Rahmutulla, 覃 睿, 中島誠也, 喜多和子, 鈴木孝禎, 根本哲宏, 金田篤志.
Organizer
第41回分子生物学会年会
Related Report
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