Novel approach to selective modification of histone methylation using DNA-binding small molecules
Project/Area Number |
17K01959
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Chemical biology
|
Research Institution | Chiba University |
Principal Investigator |
|
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)
Research Products
(16 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
Related 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
Related 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
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
-
[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
-
-
-
[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
Int'l Joint Research
-
-
-
-