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Novel approach to selective modification of histone methylation using DNA-binding small molecules

Research Project

Project/Area Number 17K01959
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Chemical biology
Research InstitutionChiba University

Principal Investigator

Shinohara Ken-ichi  千葉大学, 大学院医学研究院, 助教 (70378561)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsエピゲノム制御 / 核酸化学 / 遺伝子発現制御 / ヒストンメチル化 / ピロール・イミダゾールポリアミド / 発現制御
Outline of Final Research Achievements

Lysine-specific demethylase 1 (LSD1) inhibitors are promising as a new type of anti-cancer drug. In this study, we aimed to develop novel anti-cancer drugs by fusing LSD1 inhibitor to pyrrole-imidazole polyamides (PIP), which are small molecules that can recognize DNA sequences, in order to enhance efficiency of LSD1 inhibitors.
In the cancer cells treated with the LSD1 inhibitor alone, the genomic regions with GC-rich sequence were the main target. In other hands, AT-rich regions were targetable by PIP-LSD1 inhibitor that binds to the AT-rich DNA sequence. These results suggest that a fusion with PIP could be a new epigenome-regulating anti-cancer drug.

Academic Significance and Societal Importance of the Research Achievements

細胞の運命は、染色体上のDNA配列によるゲノム情報と、その周辺の化学的修飾であるエピゲノム情報に制御されている。本研究により、PIP-LSD1阻害剤の融合分子によって、ヒストンメチル化を選択的に制御できる新規概念が構築された。これら融合分子を用いてエピゲノム情報を改変する手法は、がんだけでなく様々な疾患治療に対しても有用性を見出すことができる。さらに、現時点で未解明な部分の多いヒストンメチル化のエピゲノム情報解析を大きく進歩させるツールとしても利用価値が高い上、細胞リプログラムやウィルス感染治療等にも応用が可能である等、極めて広い分野への波及効果が期待できる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (16 results)

All 2019 2018 2017 Other

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [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
    • Journal Title

      Heterocycles

      Volume: - Issue: 2 Pages: 891-905

    • DOI

      10.3987/com-18-s(f)57

    • Related Report
      2019 Annual Research Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 50 Pages: 29316-29335

    • DOI

      10.18632/oncotarget.25451

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Frequent promoter hypermethylation associated with human papillomavirus infection in pharyngeal cancer.2017

    • Author(s)
      Nakagawa T, Matsusaka K, Misawa K, Ota S, Takane K, Fukuyo M, Rahmutulla B, Shinohara K, Kunii N, Sakurai D, Hanazawa T, Matsubara H, Nakatani Y, Okamoto Y, Kaneda A.
    • Journal Title

      Cancer Letters

      Volume: 407 Pages: 21-31

    • DOI

      10.1016/j.canlet.2017.08.008

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of Pyrrole-Imidazole Polyamide Oligomers Based on a Copper-Catalyzed Cross-Coupling Strategy.2017

    • Author(s)
      Shiga N, Takayanagi S, Muramoto R, Murakami T, Qin R, Suzuki Y, Shinohara K, Kaneda A, Nemoto T.
    • Journal Title

      Bioorg Med Chem Lett,

      Volume: 27 Issue: 10 Pages: 2197-2200

    • DOI

      10.1016/j.bmcl.2017.03.052

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] ZAR1 knockdown promotes the differentiation of human neuroblastoma cells by suppression of MYCN expression2017

    • Author(s)
      Watanabe Yosuke、Ishizuka Yoshiaki、Hirano Takayuki、Nagasaki-Maeoka Eri、Hoshi Reina、Yoshizawa Shinsuke、Uekusa Shota、Kawashima Hiroyuki、Sugito Kiminobu、Shinohara Kenichi、Fukuda Noboru、Nagase Hiroki、Soma Masayoshi、Koshinaga Tsugumichi、Fujiwara Kyoko
    • Journal Title

      Med Oncol

      Volume: 34 Issue: 9 Pages: 158-158

    • DOI

      10.1007/s12032-017-0999-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ゲノム領域選択的なエピゲノム制御アプローチ2017

    • Author(s)
      篠原憲一、金田篤志
    • Journal Title

      Medical Science Digest

      Volume: 43 Pages: 72-75

    • Related Report
      2017 Research-status Report
  • [Presentation] がんエピゲノム異常に焦点を当てた塩基配列選択的 DNA 結合小分子の開発2019

    • Author(s)
      篠原憲一, 依田夏美, 覃睿, 福世真樹, 岡部篤史, 中島誠也, 鈴木孝禎, Rahmutulla Bahityar, 根本哲宏, 金田篤志
    • Organizer
      第13回日本エピジェネティクス研究会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] PIP-LSD1選択的阻害剤ハイブリッド分子の合成と機能評価2019

    • Author(s)
      Rui Qin,高柳志穂理,滋賀直樹,Kokiladevi Alagarswamy,篠原憲一,鈴木孝禎,金田篤志,根本哲宏
    • Organizer
      日本薬学会 第139年会
    • Related Report
      2018 Research-status Report
  • [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
      2018 Research-status Report
  • [Presentation] DNA結合小分子とLSD1阻害剤の融合化合物による新規エピゲノム標的薬剤の開発2018

    • Author(s)
      依田夏美, 篠原憲一, 岡部篤史, 根本哲宏, 福世真樹, 喜多和子, 金田篤志
    • Organizer
      平成30年度関東研究医養成コンソーシアム 第9回夏のリトリート
    • Related Report
      2018 Research-status Report
  • [Presentation] 癌エピゲノム異常の制御を目指した塩基配列選択的DNA結合小分子の開発2018

    • Author(s)
      篠原憲一, 依田夏美, 覃 睿, 福世真樹, 岡部篤史, Alagarswamy Kokiladevi, 仲野駿一, 鈴木孝禎, 根本哲宏, 金田篤志
    • Organizer
      第27回日本癌病態治療研究会
    • Related Report
      2018 Research-status Report
  • [Presentation] LSD1 Inhibitor Conjugated with PI Polyamide Enhances Region Specific Activation of Genomic Regions2018

    • 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
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] PIP-LSD1選択的阻害剤ハイブリッド分子の合成と機能評価2018

    • Author(s)
      覃睿、高柳志穂里, 滋賀直樹、Alagarswamy KOKILADEVI、篠原憲一、鈴木孝禎、金田篤志、根本哲宏
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] DNA配列を認識する小分子による選択的 DNAメチル化阻害2017

    • Author(s)
      篠原憲一、依田夏美、福世真樹、喜多和子、根本哲宏、金田篤志
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report
  • [Remarks] 千葉大学大学院 医学研究院 分子腫瘍学ホームページ

    • URL

      http://www.m.chiba-u.ac.jp/class/moloncol/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 千葉大学大学院 医学研究院 分子腫瘍学ホームページ

    • URL

      http://www.m.chiba-u.ac.jp/class/moloncol/

    • Related Report
      2018 Research-status Report 2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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