RRC ID |
67765
|
Author |
Shams R, Matsukawa A, Ochi Y, Ito Y, Miyatake H.
|
Title |
In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1.
|
Journal |
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.
|
Volume |
65(2)
|
Pages |
1329-1341
|
Published |
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
|
Resource |
Human and Animal Cells |
MCF7(RCB1904)
Hep G2
293(RCB1637)
NRK49F(RCB0112)
A549
HeLa |