タンキラーゼ抑制はアクシンを安定させ,Wntシグナル伝達を阻害する

Shih-Min A Huang¹, Yuji M Mishina, Shanming Liu

¹Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.

Nature

|September 18, 2009

まとめ

新しい分子XAV939は,Wnt経路の重要なタンパク質であるアクシンを安定させることで,がんを標的とする. これはβ-カテニンの分解を促進し,がんの成長を抑制し,新しい治療戦略を提供する.

科学分野:

分子生物学は分子生物学である.
癌生物学癌生物学について
ドラッグ・ディスカバリー・ディスカバリー・ドラッグ・ディスカバリー・ドラッグ・ディスカバリー

背景:

Wnt経路は細胞発育に不可欠であり,がんでは頻繁に失調する.
ベータ-カテニンの安定性は破壊複合体によって厳しく制御され,がんの標的となる.
Wnt経路をターゲットにすることは,薬効性のあるコンポーネントが限られているため,困難です.

研究の目的:

ベータ-カタニン媒介の転写を阻害する小分子を特定する.
新しいWnt経路阻害剤の作用メカニズムを解明する.

主な方法:

XAV939.9を特定するための化学遺伝子スクリーニング.
XAV939の標的を特定するための定量化学プロテオミクス.
アクシンタンパク質ホメオスタシスと分解経路の分析.

主要な成果:

XAV939は,アクシンを安定させることで,ベータ-カテニンの転写を選択的に抑制します.
XAV939は,アクシン分解を促進するタンキラーゼ1とタンキラーゼ2の酵素を阻害します.
タンキラーゼ抑制は,アクシン濃度の上昇と,ユビキチン-プロテアゾーム経路経由でβ-カタニンの分解につながります.

結論:

XAV939は,軸索の安定性をターゲットにすることで,新しい治療戦略を提供します.
タンキラーゼを阻害することは,Wnt経路主導のがん治療のための新しいアプローチを提供します.
アクシン調節の理解は,がん治療の新たな道を開く.

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