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

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.