Journal of medicinal chemistry, 2022-01, Vol.65 (2), p.1329-1341
2022
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Details
- Autor(en) / Beteiligte
- Titel
- In Silico and In Cell Hybrid Selection of Nonrapalog Ligands to Allosterically Inhibit the Kinase Activity of mTORC1
- Ist Teil von
- Journal of medicinal chemistry, 2022-01, Vol.65 (2), p.1329-1341
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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, , identified by a hybrid strategy of in silico and in cell selections. Our studies showed that 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. inhibited the phosphorylation of not only the ribosomal protein S6 kinase 1 (S6K1) but also eIF4E-binding protein-1 (4E-BP1). Hence, efficiently suppressed tumor growth in mice without promotion of metastasis. These results suggest that is a potent lead compound for developing anticancer drugs discovered by in silico and in cell methods.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0022-2623eISSN: 1520-4804DOI: 10.1021/acs.jmedchem.1c00536Titel-ID: cdi_proquest_miscellaneous_2547533770
- Format
- –
- Schlagworte
- 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