title: 2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency.
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.
authors.affiliation: 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.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schulte
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Dawson
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Sam A
authors.initials: SA
authors.lastname: Saleh
authors.affiliation: Hume-Fogg Academic High School, Metropolitan Nashville Public Schools, Nashville, TN 37203, United States.
authors.forename: Madison L
authors.initials: ML
authors.lastname: Cuthbertson
authors.affiliation: 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.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
mesh_terms: D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D000813:Anilides / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015778:Minor Histocompatibility Antigens; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D026962:Amino Acid Transport System ASC; D000813:Anilides; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human
keywords: ASCT2; Cancer; Glutamine; Metabolism; SLC1A5