Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters
- PMID: 31231029
- DOI: 10.1016/j.chembiol.2019.05.009
Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters
Abstract
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.
Keywords: 4E-BP1; Akt; GLUT; GLUT1; S6K1; mTOR; mTORC1; pharmacological inhibition; rapalog; rapamycin.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Comment in
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How Sweet It Is: Small-Molecule Inhibitors of mTORC1 Glucose Sensing.Cell Chem Biol. 2019 Sep 19;26(9):1195-1196. doi: 10.1016/j.chembiol.2019.09.001. Cell Chem Biol. 2019. PMID: 31539502
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