論文

国際誌
2021年6月30日

In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1.

Journal of medicinal chemistry
  • Raef Shams
  • ,
  • Akihiro Matsukawa
  • ,
  • Yukari Ochi
  • ,
  • Yoshihiro Ito
  • ,
  • Hideyuki Miyatake

65
2
開始ページ
1329
終了ページ
1341
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1021/acs.jmedchem.1c00536

Cancer-specific metabolic alterations hyperactivate the kinase activity of the mammalian/mechanistic target of rapamycin (mTOR) for overcoming stressful environments. Rapalogs, which allosterically inhibit mTOR complex 1 (mTORC1), have been approved as anticancer agents. However, the immunosuppressive side effect of these compounds results in the promotion of tumor metastasis, thereby limiting their therapeutic efficacy. We first report a nonrapalog inhibitor, WRX606, identified by a hybrid strategy of in silico and in cell selections. Our studies showed that WRX606 formed a ternary complex with FK506-binding protein-12 (FKBP12) and FKBP-rapamycin-binding (FRB) domain of mTOR, resulting in the allosteric inhibition of mTORC1. WRX606 inhibited the phosphorylation of not only the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 (4E-BP1). Hence, WRX606 efficiently suppressed tumor growth in mice without promotion of metastasis. These results suggest that WRX606 is a potent lead compound for developing anticancer drugs discovered by in silico and in cell methods.

リンク情報
DOI
https://doi.org/10.1021/acs.jmedchem.1c00536
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34191518
ID情報
  • DOI : 10.1021/acs.jmedchem.1c00536
  • PubMed ID : 34191518

エクスポート
BibTeX RIS