LAUSR

Graphical abstract Figure. No Caption available. Abstract l‐Type amino acid transporter 1 (LAT1) is a sodium‐independent exchanger transporting large neural amino acids and several amino‐acid mimicking drugs across the cell membranes. LAT1 is highly expressed at the blood brain barrier (BBB) and in numerous cancer cells and is therefore a potential drug target. However, structural features affecting the ability to bind to LAT1 and the cellular translocation by LAT1 are unclear. In the present study we determined the binding to and transport through human LAT1 of several compounds into the human breast adenocarcinoma cells (MCF‐7). We show that the meta‐conjugation of l‐phenylalanine increases binding to human LAT1 compared to para‐conjugation or aliphatic amino acid moiety. Furthermore, large, rigid and aromatic meta‐substituted l‐phenylalanine derivative enabled selective and efficient LAT1‐mediated cellular uptake. Our results also demonstrates that in addition to binding studies, it is of utmost importance to determine the cellular accumulation of compounds. It provides crucial information on transport efficiency and selectivity of transport mechanisms that the compounds are able to utilize. Overall, these structural findings and the methodology used herein are exploitable to design LAT1‐utilizing compounds, such as markers for cancer imaging and drug molecules, enabling more effective and safer treatments for cancer in the future.