ビスホスフォナート生成のATPアナログは細胞信号伝達経路を阻害する
Satish R Malwal1, Bing O'Dowd1, Xinxin Feng1
1Department of Chemistry , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
Journal of the American Chemical Society
|May 23, 2018
まとめ
骨粗鬆症と癌に使用されるビスホスフォネートは,ATPの類似体を形成することによってキナーゼを阻害する. 新しいビスホスフォナート前薬は強力なキナーゼ阻害剤を産生し,骨疾患や癌に対する薬の開発を進める.
科学分野:
- 生物化学
- 薬理学について
- 薬剤化学
背景:
- ビスホスフォネートは,骨粗鬆症,パジェット病,がんに対する重要な治療薬である.
- 提案された作用メカニズムは,タンパク質のプレニル化,EGFR,またはアデニンヌクレオチドトランスロケースの抑制を含みます.
- アデニンヌクレオチドトランスロカース抑制は,ApppIとAppCCl2pのようなATPアナログの細胞形成を伴う.
研究 の 目的:
- ビスフォスフォナート製のATPアナログのキナーゼ阻害プロフィールを調査する.
- 新しいキナーゼ阻害剤としてのビスホスフォナート前薬の可能性を調査する.
- ビスホスフォン酸媒介キナーゼ阻害の基礎にある分子相互作用を明らかにする.
主な方法:
- ApppIとAMP-クロドロナート (AppCCl2p) のスクリーニングは369基ナゼのパネルに対して行われます.
- ビスホスフォナート前薬の合成と細胞評価
- キナーゼ阻害と細胞信号伝達経路の分析
主要な成果:
- AppCCl2pは,チロシン残留物との水素結合に起因する特定のチロシンキナーズの強力な阻害を示した.
- 合成されたビスホスフォナート前薬は細胞内からATP同類に変換された.
- これらの新しいアナログは低ナノモラーキナーゼ阻害剤として作用し,細胞信号伝達経路を効果的に抑制しました.
結論:
- この発見は,キナーゼ阻害剤としてのビスホスフォネートの作用機構を明らかにする.
- ビスフォスフォナート前薬は,新しい治療薬の開発に有望な戦略です.
- この研究は骨の再吸収,癌,炎症を標的とした 新薬の発見の道を開きます
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