Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters
| Autor: | Eddine Saiah, George P. Vlasuk, Seong A. Kang, Stephanie N. Galda, Shomit Sengupta, Jessica J. Howell, Lisa Molz, David John O'neill, Sarah J. Mahoney, Andreas W. Machl, Seung Hahm, Casey J. Lumpkin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Glucose uptake Clinical Biochemistry Drug Evaluation Preclinical Glucose Transport Proteins Facilitative P70-S6 Kinase 1 Mechanistic Target of Rapamycin Complex 2 mTORC1 Mechanistic Target of Rapamycin Complex 1 01 natural sciences Biochemistry mTORC2 Mice Cell Line Tumor Drug Discovery Animals Humans Phosphorylation Molecular Biology Mechanistic target of rapamycin Protein kinase B Cell Proliferation Sirolimus Pharmacology biology 010405 organic chemistry Glucose transporter High-Throughput Screening Assays 0104 chemical sciences Mice Inbred C57BL Glucose Multiprotein Complexes biology.protein Molecular Medicine GLUT1 biological phenomena cell phenomena and immunity Proto-Oncogene Proteins c-akt Signal Transduction Transcription Factors |
| Zdroj: | Cell Chemical Biology. 26:1203-1213.e13 |
| ISSN: | 2451-9456 |
| Popis: | Summary The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor. |
| Databáze: | OpenAIRE |
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