Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5480-5. doi: 10.1073/pnas.1218165110. Epub 2013 Mar 18.


The Large-neutral Amino Acid Transporter 1 (LAT-1)--a sodium-independent exchanger of amino acids, thyroid hormones, and prescription drugs--is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amines / metabolism
  • Analysis of Variance
  • Blood-Brain Barrier / metabolism*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclohexanecarboxylic Acids / metabolism
  • Drug Delivery Systems / methods*
  • Flow Cytometry
  • Gabapentin
  • Glioblastoma / metabolism
  • HEK293 Cells
  • Humans
  • Isoxazoles / pharmacokinetics
  • Large Neutral Amino Acid-Transporter 1 / chemistry*
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Leucine / metabolism
  • Ligands
  • Models, Molecular*
  • Tritium
  • gamma-Aminobutyric Acid / metabolism


  • Amines
  • Cyclohexanecarboxylic Acids
  • Isoxazoles
  • Large Neutral Amino Acid-Transporter 1
  • Ligands
  • Tritium
  • gamma-Aminobutyric Acid
  • Gabapentin
  • Leucine
  • acivicin