Skip to Content
MilliporeSigma
  • Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

Cell chemical biology (2019-06-25)
Seong A Kang, David J O'Neill, Andreas W Machl, Casey J Lumpkin, Stephanie N Galda, Shomit Sengupta, Sarah J Mahoney, Jessica J Howell, Lisa Molz, Seung Hahm, George P Vlasuk, Eddine Saiah
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Ribonuclease A from bovine pancreas, Type II-A, ≥60% (SDS-PAGE), >= 60 Kunitz units/mg protein
Sigma-Aldrich
Cytochalasin B from Drechslera dematioidea, ≥98% (HPLC), powder
SAFC
CHO Feed Bioreactor Supplement, Animal Component-free, solution, sterile-filtered, suitable for cell culture
Sigma-Aldrich
2-Fluoro-2-deoxy-D-glucose, glycosylation inhibitor, glucose analog
Sigma-Aldrich
Fluorescein di(β-D-galactopyranoside)
Sigma-Aldrich
Debrisoquine sulfate
Supelco
Rotenone, PESTANAL®, analytical standard
Sigma-Aldrich
NV-5440, ≥98% (HPLC)
Sigma-Aldrich
Rotenone, ≥95%