Novel alanine serine cysteine transporter 2 (ASCT2) inhibitors based on sulfonamide and sulfonic acid ester scaffolds
| Autor: | Paul Zakrepine, Rachel-Ann A. Garibsingh, Jiali Wang, Christof Grewer, Avner Schlessinger, Evan Wallace, Yueyue Shi, Elias Ndaru |
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| Rok vydání: | 2019 |
| Předmět: |
Amino Acid Transport System ASC
0301 basic medicine Physiology Stereochemistry Glutamine transport Minor Histocompatibility Antigens Serine 03 medical and health sciences 0302 clinical medicine Membrane Transport Modulators Humans Research Articles chemistry.chemical_classification Alanine Sulfonamides Binding Sites Communication Esters 3. Good health Amino acid Sulfonamide Molecular Docking Simulation Glutamine HEK293 Cells 030104 developmental biology chemistry 030220 oncology & carcinogenesis Amino acid binding Sulfonic Acids Protein Binding Cysteine |
| Zdroj: | The Journal of General Physiology |
| ISSN: | 1540-7748 0022-1295 |
| DOI: | 10.1085/jgp.201812276 |
| Popis: | ASCT2 is a transporter that exchanges neutral amino acids such as glutamine across the cell membrane, an essential process for rapidly growing cells, including cancerous ones. Ndaru et al. report the synthesis and characterization of a novel class of inhibitors useful for studying this transporter. 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, Ki, of 8 ± 4 µM and can block the alanine response with a Ki 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. |
| Databáze: | OpenAIRE |
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