Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2
Graphical abstract
Section snippets
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.
References (22)
J Nutr
(2001)- et al.
J Biol Chem
(1992) - et al.
Semin Cancer Biol
(2005) - et al.
Cell
(2009) - et al.
Pharmacol Ther
(2009) - et al.
Bioorg Med Chem
(2005) - et al.
Bioorg Med Chem Lett
(2015) - et al.
Bioorg Med Chem Lett
(2016) - et al.
Amino acid transporters and glutamine
- et al.
Pflugers Arch – Eur J Physiol
(2004)
Biochem J
Cited by (24)
Design strategies and recent development of bioactive modulators for glutamine transporters
2024, Drug Discovery TodayAlanine serine cysteine transporter (ASCT) substrate binding site properties probed with hydroxyhomoserine esters
2022, Journal of Physical Organic ChemistryDiseases & disorders: Therapies targeting glutamine addiction in cancer
2021, Encyclopedia of Biological Chemistry: Third EditionTarget the human Alanine/Serine/Cysteine Transporter 2(ASCT2): Achievement and Future for Novel Cancer Therapy
2020, Pharmacological ResearchCitation Excerpt :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 transporters as pharmacological targets: From function to drug design
2020, Asian Journal of Pharmaceutical SciencesCitation Excerpt :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].
Advances and Challenges in Rational Drug Design for SLCs
2019, Trends in Pharmacological SciencesCitation Excerpt :Further, virtual screening of large compound libraries from the ZINC databaseiii, combined with cellular uptake and electrophysiology assays, identified new ASCT2 ligands, including five substrate-like compounds and two ASCT2 inhibitors (e.g., γ-2-fluorobenzyl proline) [44]. This study highlighted the utility of virtual screening to capture unexplored chemical spaces of transporter ligands, which have been further optimized to obtain higher-affinity inhibitors [51]. Subsequent ASCT2 models based on the human EAAT1 structure [27] (sequence identity of 46%) provided a refined conformation of TM8 and hairpin 2 (HP2) and overall a more accurate model, as measured by various measures such as its ability to enrich known ligands compared with decoy molecules [52].
- 1
Current address: Department of Chemistry and Physics and Vascular Biology Center, Augusta University, Augusta, GA 30912, United States.