The Evaluation of L-Tryptophan Derivatives as Inhibitors of the LType Amino Acid Transporter LAT1 (SLC7A5).

Graff, Julien; Müller, Jennifer; Sadurní, Anna; Rubin, Matthias; Cuissa, Inês André Canivete; Keller, Claudia; Hartmann, Marco; Singer, Simon; Gertsch, Jürg; Altmann, Karl-Heinz (2022). The Evaluation of L-Tryptophan Derivatives as Inhibitors of the LType Amino Acid Transporter LAT1 (SLC7A5). ChemMedChem, 17(17), e202200308. Wiley-VCH 10.1002/cmdc.202200308

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A series of derivatives of the substrate amino acid Ltryptophan 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 7benzyloxy-L-tryptophans, the 5-substituted derivative was the most potent, with an IC 50 of 19 μM for inhibition of [ 3 H]-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 substrates of LAT1-mediated transport.

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