Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

doi:10.1016/j.bmcl.2016.12.063

Bioorganic & Medicinal Chemistry Letters

Volume 27, Issue 3, 1 February 2017, Pages 398-402

https://doi.org/10.1016/j.bmcl.2016.12.063 Get rights and content

Abstract

The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a K_i of 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.

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Acknowledgements

This study was supported by a grant from the National Institutes of Health (http://www.nih.gov) (R01 GM108911) to AS, CC and CG.

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These molecules which are designed based on rat ASCT2, are effective on inhibition of ASCT2 overexpressed even in human cell. In brief, it was suggested that benzylproline scaffold can provide a valuable tool to the understanding of the molecular parameters and the design of new and more efficient inhibitors against human ASCT2 [115]. In search of compounds with the ability to inhibit ASCT1/2, Alan C. Foster and co-workers screened a set of amino acid analogs and found that PG analogs with the ability to selectively and effectively inhibit ASCT1 and ASCT2.
Glutamine metabolism, described as major energy and building blocks supply to cell growth, has gained great attention. Alanine-Serine-Cysteine Transporter (ASCT2), which belongs to solute carried (SLC) family transporters and is encoded by the SLC1A5 gene serves as a significant role for glutamine transport. Indeed, ASCT2 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, ASCT2 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that ASCT2 inhibitors can provide a benefit strategy for cancer therapy. Herein, we describe the structure of ASCT2, and summarize its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for ASCT2 inhibitors. On the basis of case studies, our perspectives for targeting ASCT2 and development of ASCT2 antagonist are discussed in the final part.
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These compounds, even if designed on rat ASCT2, showed cytotoxic effects also on human melanoma cell line [45]. Moving from this indication, the benzyl proline derivatives constituted the scaffold for designing more efficient inhibitors specific for the human ASCT2 and a Ki in the micromolar range has been measured in human cells for these compounds [46]. In another study, a competitive inhibitor of human ASCT2 has been identified starting from a previous screening conducted on 2-amino-4-bis (aryloxybenzyl)aminobutanoic acid derivatives [47].
Among the different targets of administered drugs, there are membrane transporters that play also a role in drug delivery and disposition. Moreover, drug-transporter interactions are responsible for off-target effects of drugs underlying their toxicity. The improvement of the drug design process is subjected to the identification of those membrane transporters mostly relevant for drug absorption, delivery and side effect production. A peculiar group of proteins with great relevance to pharmacology is constituted by the membrane transporters responsible for managing glutamine traffic in different body districts. The interest around glutamine metabolism lies in its physio-pathological role; glutamine is considered a conditionally essential amino acid because highly proliferative cells have an increased request of glutamine that cannot be satisfied only by endogenous synthesis. Then, glutamine transporters provide cells with this special nutrient. Among the glutamine transporters, SLC1A5, SLC6A14, SLC6A19, SLC7A5, SLC7A8 and some members of SLC38 family are the best characterized, so far, in both physiological and pathological conditions. Few 3D structures have been solved by CryoEM; other structural data on these transporters have been obtained by computational analysis. Interactions with drugs have been described for several transporters of this group. For some of them, the studies are at an advanced stage, for others, the studies are still in nuce and novel biochemical findings open intriguing perspectives.
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¹: Current address: Department of Chemistry and Physics and Vascular Biology Center, Augusta University, Augusta, GA 30912, United States.

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Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

Abstract

Graphical abstract

Section snippets

Acknowledgements

J Nutr

J Biol Chem

Semin Cancer Biol

Cell

Pharmacol Ther

Bioorg Med Chem

Bioorg Med Chem Lett

Bioorg Med Chem Lett

Amino acid transporters and glutamine

Pflugers Arch – Eur J Physiol

Biochem J