Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 2, Pages 1329-1341Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00536
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Funding
- Junior Research Associate (JRA) Program in RIKEN
- Incentive Research Program in RIKEN (FY2018-2019)
- JSPS [JP20K06516]
- Incentive Research Program in RIKEN (FY2019-2020)
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This study reports a novel nonrapalog inhibitor, WRX606, which efficiently inhibits tumor growth without promoting metastasis by forming a ternary complex with mTOR protein. This finding provides important insights for the development of more effective anticancer drugs.
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 FKB-Prapamycin-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.
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