| 作成者 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 本文言語 |
|
| 出版者 |
|
| 発行日 |
|
| 収録物名 |
|
| 巻 |
|
| 号 |
|
| 開始ページ |
|
| 終了ページ |
|
| アクセス権 |
|
| 権利関係 |
|
|
|
| 関連DOI |
|
| 関連URI |
|
| 概要 |
The choice of an appropriate electrophile is crucial in the design of targeted covalent inhibitors (TCIs). In this report, we systematically investigated the glutathione (GSH) reactivity of various ha...loacetamides and the aqueous stability of their thiol adducts. Our findings revealed that dihaloacetamides cover a broad range of GSH reactivity depending on the combination of the halogen atoms and the structure of the amine scaffold. Among the dihaloacetamides, dichloroacetamide (DCA) exhibited slightly lower GSH reactivity than chlorofluoroacetamide (CFA). The DCA–thiol adduct is readily hydrolyzed under aqueous conditions, but it can stably exist in the solvent-sequestered binding pocket of the protein. These reactivity profiles of DCA were successfully exploited in the design of TCIs targeting noncatalytic cysteines of KRAS^<G12C> and EGFR^<L858R/T790M>. These inhibitors exhibited strong antiproliferative activities against cancer cells. Our findings provide valuable insights for designing dihaloacetamide-based reversible covalent inhibitors.続きを見る
|
Mendeley出力
