Dataset Information

Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.

ABSTRACT: The neutral amino acid transporter alanine serine cysteine transporter 2 (ASCT2) belongs to the solute carrier 1 (SLC1) family of transport proteins and transports neutral amino acids, such as alanine and glutamine, into the cell in exchange with intracellular amino acids. This amino acid transport is sodium dependent, but not driven by the transmembrane Na+ concentration gradient. Glutamine transport by ASCT2 is proposed to be important for glutamine homoeostasis in rapidly growing cancer cells to fulfill the energy and nitrogen demands of these cells. Thus, ASCT2 is thought to be a potential anticancer drug target. However, the pharmacology of the amino acid binding site is not well established. Here, we report on the synthesis and characterization of a novel class of ASCT2 inhibitors based on an amino acid scaffold with a sulfonamide/sulfonic acid ester linker to a hydrophobic group. The compounds were designed based on an improved ASCT2 homology model using the human glutamate transporter hEAAT1 crystal structure as a modeling template. The compounds were shown to inhibit with a competitive mechanism and a potency that scales with the hydrophobicity of the side chain. The most potent compound binds with an apparent affinity, K i, of 8 ± 4 µM and can block the alanine response with a K i of 40 ± 23 µM at 200 µM alanine concentration. Computational analysis predicts inhibitor interactions with the binding site through molecular docking. In conclusion, the sulfonamide/sulfonic acid ester scaffold provides facile synthetic access to ASCT2 inhibitors with a potentially large variability in chemical space of the hydrophobic side chain. These inhibitors will be useful chemical tools to further characterize the role of ASCT2 in disease as well as improve our understanding of inhibition mechanisms of this transporter.

SUBMITTER: Ndaru E

PROVIDER: S-EPMC6400523 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.

Ndaru Elias E Garibsingh Rachel-Ann A RA Shi YueYue Y Wallace Evan E Zakrepine Paul P Wang Jiali J Schlessinger Avner A Grewer Christof C

The Journal of general physiology 20190204 3

The neutral amino acid transporter alanine serine cysteine transporter 2 (ASCT2) belongs to the solute carrier 1 (SLC1) family of transport proteins and transports neutral amino acids, such as alanine and glutamine, into the cell in exchange with intracellular amino acids. This amino acid transport is sodium dependent, but not driven by the transmembrane Na<sup>+</sup> concentration gradient. Glutamine transport by ASCT2 is proposed to be important for glutamine homoeostasis in rapidly growing c ...[more]

PMID: 30718375

Similar Datasets

Project description:PurposeTo evaluate the expression of alanine-serine-cysteine-transporter 2 (ASCT2) and L-type amino acid transporter1 (LAT1) in prostate cancer (PCa) and their impact on uptake of 18F-1-amino-3-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) which is approved for the detection of recurrent PCa.MethodsTwenty-five hormone-naïve patients with histologically confirmed PCa underwent PET/CT before prostatectomy. Dynamic imaging was performed immediately after injection of 368 ± 10 MBq of 18F-fluciclovine and the uptake in PCa was expressed as SUVmax at six sequential 4-min time frames and as tracer distribution volume (VT) using Logan plots over 0-24 min. The expression of ASCT2 and LAT1 was studied with immunohistochemistry (IHC) on a tissue microarray (TMA) containing three cores per carcinoma lesion. The TMA slides were scored independently by two trained readers based on visual intensity of ASCT2/LAT1 expression on a four-tiered scale. The correlations between ASCT2/LAT1 staining intensity, SUVmax/VT, and Gleason grade group (GGG) were assessed using Spearman's rank correlation coefficient (ρ).ResultsForty tumor foci (> 0.5 mm in diameter, max. 3 per patient) were available for TMA. In visual scoring, low, moderate, and high staining intensity of ASCT2 was observed in 4 (10%), 24 (60%), and 12 (30%) tumors, respectively. No tumors showed high LAT1 staining intensity while moderate intensity was found in 10 (25%), 25 (63%) showed low, and the remaining 5 (12%) were negative for staining with LAT1. Tumors with GGG > 2 showed significantly higher uptake of 18F-fluciclovine and higher LAT1 staining intensity (p < 0.05). The uptake of 18F-fluciclovine correlated significantly with LAT1 expression (ρ = 0.39, p = 0.01, for SUVmax at 2 min and ρ = 0.39, p = 0.01 for VT). No correlation between ASCT2 expression and 18F-fluciclovine uptake or GGG was found.ConclusionsOur findings suggest that LAT1 is moderately associated with the transport of 18F-fluciclovine in local PCa not exposed to hormonal therapy. Both high and low Gleason grade tumors express ASCT2 while LAT1 expression is less conspicuous and may be absent in some low-grade tumors. Our observations may be of importance when using 18F-fluciclovine imaging in the planning of focal therapies for PCa.

Dataset Information

Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.

Publications

Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets