2019 Fiscal Year Final Research Report
Chemical epigenetics of histone mutations in cancer: development of lysine methyltransferase modulators
| Project/Area Number |
16K18913
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Drug development chemistry
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | ケミカルエピジェネティクス / ヒストンメチル化 / ポリコーム抑制複合体２ / ヒストン変異 |
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| Outline of Final Research Achievements |
We aimed to develop histone H3K27 methyltransferase modulators with focusing on H3K27M-mutant pediatric gliomas. The project for the study on development of positive modulators of H3K27 methylation, a linear peptide, which has affinity for EED, was structurally optimized and a cyclic peptide derivative that exhibited potent PRC2 activator activity was obtained. The existence of intramolecular hydrogen bonds in the cyclic peptide was suggested to be important for the specific secondary structure inducing the PRC2 stimulation. In addition, we tried to find molecules that have affinity to the histone H3K27M protein by using compound arrays. Some molecules showed affinity to the target protein, however resynthesized compounds did not show avidity to the mutated protein with good reproducibility.
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| Free Research Field |
ケミカルエピジェネティクス
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| Academic Significance and Societal Importance of the Research Achievements |
ヒストン H3K27M 変異が報告されて以来、小児脳幹グリオーマの新規治療法開発が盛んに行われており、H3K27 メチル化増加を目的とした脱メチル化酵素阻害剤の探索が主流になっている。一方、申請者は独自のアプローチとして PRC2 活性促進剤および H3K27M 機能阻害剤を見出すことで H3K27 メチル化増加を狙う点を特色としており、エピゲノム創薬分野において高い新規性、独創性を有している。現在細胞評価系でも有効な PRC2 活性促進剤および H3K27M 機能阻害剤は報告例がないことから、新規化学プローブの獲得および新規治療薬創製への展開が期待される。
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