論文 - 詳細
| RRC ID | 67765 |
|---|---|
| 著者 | Shams R, Matsukawa A, Ochi Y, Ito Y, Miyatake H. |
| タイトル | In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1. |
| ジャーナル | J Med Chem |
| Abstract |
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. |
| 巻・号 | 65(2) |
| ページ | 1329-1341 |
| 公開日 | 2022-1-27 |
| DOI | 10.1021/acs.jmedchem.1c00536 |
| PMID | 34191518 |
| MeSH | Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Allosteric Regulation Animals Apoptosis Breast Neoplasms / drug therapy* Breast Neoplasms / metabolism Breast Neoplasms / pathology Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Proliferation Computer Simulation* Female Humans Ligands Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors* Mice Mice, Inbred BALB C Mice, Nude Phosphorylation Protein Kinase Inhibitors / pharmacology* Ribosomal Protein S6 Kinases, 90-kDa / genetics Ribosomal Protein S6 Kinases, 90-kDa / metabolism* Signal Transduction Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| IF | 6.205 |
| リソース情報 | |
| ヒト・動物細胞 | MCF7(RCB1904) Hep G2 293(RCB1637) NRK49F(RCB0112) A549 HeLa |