2. Academic Validation
  3. 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport

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

  • Bioorg Med Chem Lett. 2016 Feb 1;26(3):1044-1047. doi: 10.1016/j.bmcl.2015.12.031.
Michael L Schulte 1,  Alexandra B Khodadadi 2,  Madison L Cuthbertson 3,  Jarrod A Smith 4,  H Charles Manning 5
Affiliations

Affiliations

  • 1 Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 2 Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 3 Hume-Fogg Academic High School, Metropolitan Nashville Public Schools, Nashville, TN 37203, United States.
  • 4 Vanderbilt Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, United States; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, United States.
  • 5 Vanderbilt Center for Molecular Probes, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, United States; Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
PMID: 26750251 DOI: 10.1016/j.bmcl.2015.12.031
Abstract

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.

Keywords

ASCT2; Cancer; Glutamine; Metabolism; SLC1A5.

Figures