Development of a Novel Class of Glucose Transporter Inhibitors

Abstract

Based on our finding that the antitumor effect of 5-(4-((1-methylcyclohexyl)methoxy)benzyl)thiazolidine-2,4-dione, a thiazolidinedione peroxisome proliferator-activated receptor (PPAR)γ agonist, was, in part, attributable to its ability to block glucose uptake independently of PPARγ, we used its PPARγ-inactive analogue to develop a novel class of glucose transporter (GLUT) inhibitors. This lead optimization led to compound 30 (5-(4-hydroxy-3-trifluoromethyl-benzylidene)-3-[4,4,4-trifluoro-2-methyl-2-(2,2,2-trifluoro-ethyl)-butyl]-thiazolidine-2,4-dione) as the optimal agent, which exhibited high antitumor potency through the suppression of glucose uptake (IC50, 2.5 μM), while not cytotoxic to prostate and mammary epithelial cells. This glucose uptake inhibition was associated with the inhibition of GLUT1 (IC50, 2 μM). Moreover, the mechanism of antitumor action of compound 30 was validated by its effect on a series of energy restriction-associated cellular responses. Homology modeling analysis suggests that the inhibitory effect of compound 30 on glucose entry was attributable to its ability to bind to the GLUT1 channel at a site distinct from that of glucose.

Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents

“…Although the side chain positions were not optimized for ligand binding in the GLUT1 homology model, the data indicate the potential for the active compounds to interact with several key residues that span the solute channel. The proposed binding mode appears to occupy a similar site predicted for both the recently reported thiazolidine 2,4-diones 24 and diphenoxybenzoates 25–27 that inhibit glucose uptake through binding to GLUT-1. In particular, the thiazolidine 2,4-diones are predicted to make an electrostatic interaction with Trp412 and Arg126 as well as form a π – π stacking interaction with Tyr28 24 Similarly, the diphenoxybenzoate WZB114 was modelled binding to Arg126 and Trp412, as well as Asn34.…”

The mRNA-stabilizing Factor HuR Protein Is Targeted by β-TrCP Protein for Degradation in Response to Glycolysis Inhibition

“…Cells were maintained and treated with individual test agents in 10% FBSsupplemented RPMI 1640 medium (Invitrogen) at 37°C in a humidified incubator containing 5% CO 2 . CG-5 was synthesized according to a published procedure (18). 2-DG, MG132, cycloheximide, and leptomycin B were purchased from SigmaAldrich (St. Louis, MO).…”

“…In this study, we demonstrate that HuR was subjected to ubiquitin-dependent degradation via a novel mechanism in prostate cancer cells in response to metabolic stress induced by glucose depletion or glycolysis inhibitors, including CG-5, a glucose transporter inhibitor (18), and 2-deoxyglucose (2-DG). Moreover, we obtained evidence that HuR was targeted for ubiquitination by the E3 ubiquitin ligase ␤-transducin repeat-* This work was supported by National Cancer Institute Public Health Service containing protein (␤-TrCP) 1 in response to glycolysis inhibition, and that PKC␣ and IB kinase (IKK) ␣ were involved in facilitating cytoplasmic translocation and ␤-TrCP1 recognition of HuR, respectively, in the course of ubiquitin-dependent degradation.…”

An update on therapeutic opportunities offered by cancer glycolytic metabolism

“…1) were developed following the observation that a peroxisome proliferator-activated receptor c (PPARc) agonist exerted part of its action through inhibition of glucose transport. 20 Compound 7 exhibited an excellent suppression of glucose uptake (IC 50 = 2.5 lM) in LNCaP prostate cancer cells. This activity led to an efficient antiproliferative activity on the same cell line, with no evident toxicity on healthy prostate and mammary epithelial cells.…”