2. Academic Validation
  3. 2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency

2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency

  • Bioorg Med Chem Lett. 2015 Jan 1;25(1):113-6. doi: 10.1016/j.bmcl.2014.10.098.
Michael L Schulte 1,  Eric S Dawson 2,  Sam A Saleh 3,  Madison L Cuthbertson 4,  H Charles Manning 5
Affiliations

Affiliations

  • 1 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 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 3 Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States.
  • 4 Hume-Fogg Academic High School, Metropolitan Nashville Public Schools, Nashville, TN 37203, United States.
  • 5 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; Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Program in Chemical and Physical Biology, 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.
PMID: 25435145 DOI: 10.1016/j.bmcl.2014.10.098
Abstract

Herein, we report the discovery and structure-activity relationships (SAR) of 2-substituted glutamylanilides as novel probes of the steric environment comprising the amino acid binding domain of alanine-serine-cysteine transporter subtype 2 (ASCT2). Focused library development led to three novel, highly potent ASCT2 inhibitors, with N-(2-(morpholinomethyl)phenyl)-L-glutamine exhibiting the greatest potency in a live-cell glutamine uptake assay. This level of potency represents a three-fold improvement over the most potent, previously reported inhibitor in this series, GPNA. Furthermore, this and Other compounds in the series exhibit tractable chemical properties for further development as potential therapeutic leads.

Keywords

ASCT2; Cancer; Glutamine; Metabolism; SLC1A5.

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