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. Epub 2014 Nov 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System ASC / antagonists & inhibitors
  • Amino Acid Transport System ASC / chemistry*
  • Amino Acid Transport System ASC / metabolism*
  • Anilides / chemistry*
  • Anilides / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Minor Histocompatibility Antigens
  • Protein Binding / physiology
  • Protein Structure, Secondary
  • Structure-Activity Relationship

Substances

  • Amino Acid Transport System ASC
  • Anilides
  • Minor Histocompatibility Antigens
  • SLC1A5 protein, human