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The Evaluation of l‐Tryptophan Derivatives as Inhibitors of the l‐Type Amino Acid Transporter LAT1 (SLC7A5)

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The attachment of a benzyloxy group to the 5-position of the indole system of the LAT1 (SLC7A5) substrate amino acid l-Trp produced a moderately potent inhibitor of LAT1-mediated leucine transport in HT-29 cells, while no inhibition of LAT1 was observed for 4-, 6-, or 7-benzyloxy-l-Trp at concentrations below 100 μM. None of these benzyloxy-l-Trp residues was found to be a transport substrate. The extension of the benzyloxy group in 5-benzyloxy-l-Trp with aryl or heteroaryl moieties in most cases did not result in significant changes in LAT1 inhibitory activity.


A series of derivatives of the substrate amino acid l-tryptophan have been investigated for inhibition of the L-type amino acid transporter LAT1 (SLC7A5), which is an emerging target in anticancer drug discovery. Of the four isomeric 4-, 5-, 6-, or 7-benzyloxy-l-tryptophans, the 5-substituted derivative was the most potent, with an IC50 of 19 μM for inhibition of [3H]-l-leucine uptake into HT-29 human colon carcinoma cells. The replacement of the carboxy group in 5-benzyloxy-l-tryptophan by a bioisosteric tetrazole moiety led to a complete loss in potency. Likewise, the corresponding tetrazolide derived from l-tryptophan itself was found to be neither a substrate nor an inhibitor of the transporter. Increasing the steric bulk at the 5-position, while reasonably well tolerated in some cases, did not result in an improvement in potency. At the same time, none of these derivatives was found to be a substrate for LAT1-mediated transport.

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