H3K36me2の減少のための強力で選択的な標的型NSD2劣化剤の発見

Ronan P Hanley¹, David Y Nie^2,3,4, John R Tabor¹

¹Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.

Journal of the American Chemical Society

|March 28, 2023

まとめ

新しい分子UNC8153は,NSD2タンパク質を効果的に分解し,H3K36me2のレベルを低下させます. 特に多発性骨髄腫では癌細胞のフェノタイプを低下させることが期待されています

科学分野:

エピジェネティクスと遺伝子調節
癌生物学
薬物の発見

背景:

核受容体結合SETドメイン含有2 (NSD2) は,ヒストンH3ライシン36二メチル化 (H3K36me2) による遺伝子調節に不可欠である.
異常なNSD2活性が様々ながんに関与していますが,選択的触媒阻害剤は依然として難解です.
NSD2を標的にすることは,NSD2主導の悪性腫瘍に対する潜在的な治療戦略です.

研究の目的:

選択的なNSD2分解のための新しい小分子を開発し,特徴づけること.
NSD2タンパク質減少のメカニズムとその下流効果を調査する.
多発性骨髄腫のモデルにおけるNSD2分解の治療の可能性を評価する.

主な方法:

新しいNSD2標的分子分解剤UNC8153の開発
細胞のNSD2タンパク質レベルとH3K36me2マークの評価
多発性骨髄腫の細胞フェノタイプ (増殖,粘着) に対するUNC8153の効果の評価 in vitro

主要な成果:

UNC8153は,細胞内のNSD2タンパク質レベルとH3K36me2マークを強力かつ選択的に低下させる.
UNC8153によるNSD2の分解は,プロテアソームに依存するメカニズムによって起こります.
UNC8153によるNSD2の分解は,多発性骨髄腫細胞の病理的表型を低下させ,抗増殖および抗粘着効果を含む.

結論:

UNC8153は,タンパク質の分解を通してNSD2を標的とする新しいアプローチを表しています.
選択的なNSD2分解は,H3K36me2のレベルを効果的に低下させ,がん細胞の行動に影響を与えます.
UNC8153は,異常なNSD2発現を有する多発性骨髄腫の治療の可能性を示しています.

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