c- Myc- Targeting PROTAC トリプルネガティブな乳がんの併用療法のためのTNA- DNAバイバルンバインダーに基づく

Xintong Li¹, Ze Zhang², Fangyan Gao¹

¹Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Journal of the American Chemical Society

|April 17, 2023

まとめ

研究者は,攻撃的な三重陰性乳がん (TNBC) の標的であるc- Mycを分解する新しい核酸PROTACを開発しました. この治療アプローチはTNBCの治療と薬の開発に有望な結果をもたらします

科学分野:

生物化学
分子生物学
ガン治療薬

背景:

トリプルネガティブ乳がん (TNBC) は,標的治療法がない攻撃的なサブタイプです.
c- Mycオンコタンパク質はTNBCの重要な原動力であり,潜在的な治療標的である.
TNBCの現在の治療戦略は限られており,新しい治療方法が必要である.

研究の目的:

c-Mycオンコタンパク質を分解する新しい核酸ベースのタンパク質分解標的キメラ (PROTAC) を開発する.
TNBC細胞の増殖を抑制し,既存の治療法に対する細胞の感受性を評価する.
臨床前TNBCモデルにおけるPROTACの治療の可能性を評価する.

主な方法:

c-Myc/Maxヘテロダイマーを標的としたTNA (トリオース核酸) アプタマーを選択する.
TNAアプタマーとEボックスDNA配列とポマリドミドを結合して二価PROTAC (TEP) を生成する.
TEP媒介によるc- Myc/ Maxの分解,TNBC細胞増殖の抑制,および薬物感受性のインビトロ評価.
マウスTNBCモデルにおけるTEPとパルボシクリブ併用療法のインビボ評価

主要な成果:

TNA-E ボックスポマリドミド (TEP) 結合剤は,内生的なc-Myc/Maxを効果的に標的とし,分解する.
TEPはTNBC細胞の増殖を in vitroで有意に抑制する.
TEPは,サイクリン依存キナーゼ阻害剤パルボシクリブに対してTNBC細胞を敏感にします.
TEPとpalbociclibを併用した治療は,マウスTNBCモデルにおける腫瘍の成長を強力に抑制する.

結論:

核酸ベースのPROTACはTNBCのような攻撃的な癌を標的とした有効な方法です.
開発されたTEPコンジュガートはTNBCの治療に有意義な可能性を示しています.
このアプローチは化学生物学の研究とTNBCの将来の臨床介入の両方にとって有望な戦略です.

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