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2019 Fiscal Year Final Research Report

Development of region-specific inhibitors against epigenomic aberrations critical for gastrointestinal tumorigenesis

Research Project

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Project/Area Number 18K19572
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research InstitutionChiba University

Principal Investigator

Kaneda Atsushi  千葉大学, 大学院医学研究院, 教授 (10313024)

Project Period (FY) 2018-06-29 – 2020-03-31
Keywords癌 / エピジェネティクス / 阻害剤 / PI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.

Free Research Field

癌エピジェネティクス

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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Published: 2021-02-19  

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