選択的なJumonji H3K27デメチラーゼ阻害剤は,炎症性マクロファージの反応を調節する
Laurens Kruidenier1, Chun-wa Chung, Zhongjun Cheng
1Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, UK.
Nature
|July 31, 2012
まとめ
研究者らは,JMJD3とUTX (KDM6サブファミリー) ヒストンデメチラゼに対する最初の選択性小分子阻害剤を開発した. この画期的な発見は,炎症におけるそれらの役割を明らかにし,関連疾患に対する標的の薬の開発を可能にします.
科学分野:
- バイオケミストリー バイオケミストリー
- エピジェネティクス エピジェネティクス
- 分子生物学は分子生物学である.
背景:
- ジュンジョンジ (JMJ) ヒストンデメチラゼは,遺伝子転写と表遺伝子遺伝を調節する.
- 細胞反応におけるJMJデメチラゼの活性性の機能的役割は,選択的阻害剤が不足しているため,十分に理解されていません.
- KDM6サブファミリー (JMJD3とUTX) は,特にH3K27me3.3をデメチラ化する.
研究 の 目的:
- 構造主導的アプローチを用いて,H3K27me3特異性デメチラゼサブファミリー (KDM6) の機能的役割を解明する.
- H3K27me3に特異的なJMJサブファミリーの選択性を持つ最初の小分子触媒部位阻害剤を開発する.
- 炎症反応の調節におけるJMJD3とUTXの役割を調査する.
主な方法:
- 構造による薬物設計と化学プロテオミクス.
- 人間とマウスのリガンド構造の決定 JMJD3.3.
- KDM6サブファミリーに選択的に作用する新しい小分子阻害剤の生成と試験.
- ヒトのマクロファージにおけるリポポリサッカリド誘発型サイトカインの産生を低減する阻害剤の有効性の評価.
主要な成果:
- KDM6デメチラゼによるコファクター,基板,および阻害剤の認識に関する新しい構造的洞察.
- H3K27me3に特異的なJMJデメチラゼの触媒部位を標的とした最初の選択性小分子阻害剤の開発.
- 阻害剤が新しい方法で結合することを示す.
- JMJD3とUTXに依存するヒトマクロファージにおける炎症性サイトカイン生成の有意な減少.
- 炎症反応におけるH3K27固有のJMJの触媒的機能の明確化.
結論:
- この研究は,疾患に関連する炎症反応におけるH3K27特異のJMJの触媒的機能に関する曖昧さを解消しています.
- 開発された小分子阻害剤は,薬理学的介入のための貴重なツールを提供します.
- これらの発見は,治療上の応用のために,より広いJMJファミリーの選択性阻害剤の設計を奨励しています.
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