H. Manning
Faculty Member
Last active: 3/22/2018

2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport.

Schulte ML, Khodadadi AB, Cuthbertson ML, Smith JA, Manning HC
Bioorg Med Chem Lett. 2016 26 (3): 1044-1047

PMID: 26750251 · PMCID: PMC4727990 · DOI:10.1016/j.bmcl.2015.12.031

Herein, we report the discovery of 2-amino-4-bis(aryloxybenzyl)aminobutanoic acids as novel inhibitors of ASCT2(SLC1A5)-mediated glutamine accumulation in mammalian cells. Focused library development led to two novel ASCT2 inhibitors that exhibit significantly improved potency compared with prior art in C6 (rat) and HEK293 (human) cells. The potency of leads reported here represents a 40-fold improvement over our most potent, previously reported inhibitor and represents, to our knowledge, the most potent pharmacological inhibitors of ASCT2-mediated glutamine accumulation in live cells. These and other compounds in this novel series exhibit tractable chemical properties for further development as potential therapeutic leads.

Copyright © 2015 Elsevier Ltd. All rights reserved.

MeSH Terms (13)

Amino Acid Transport System ASC Animals Binding Sites Butyrates Cell Line Glutamine HEK293 Cells Humans Minor Histocompatibility Antigens Molecular Docking Simulation Protein Structure, Tertiary Rats Structure-Activity Relationship

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