jm1c00536_si_002.pdf (11.47 MB)
In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1
journal contributionposted on 2021-06-30, 16:40 authored by Raef Shams, Akihiro Matsukawa, Yukari Ochi, Yoshihiro Ito, Hideyuki Miyatake
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.
potent lead compoundovercoming stressful environmentsimmunosuppressive side effectwrx606 bmice without promotionfkbp – rapamycincell hybrid selectionhybrid strategycell selectionscell methodsthereby limitingtherapeutic efficacyternary complexstudies showedresults suggestnonrapalog ligandsnonrapalog inhibitormechanistic targetkinase activityfirst reportcompounds resultsbp1 ).anticancer agentsalso eif4eallosterically inhibitallosteric inhibition