Graff, JulienJulienGraffMüller, JenniferJenniferMüllerSadurní, AnnaAnnaSadurníRubin, MatthiasMatthiasRubinCuissa, Inês André CaniveteInês André CaniveteCuissaKeller, ClaudiaClaudiaKellerHartmann, MarcoMarcoHartmannSinger, Simon AlexSimon AlexSingerGertsch, JürgJürgGertschAltmann, Karl-HeinzKarl-HeinzAltmann2024-10-112024-10-112022-09-05https://boris-portal.unibe.ch/handle/20.500.12422/86382A 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.enAmino acid transporter LAT1 inhibitor Structure-activity relationships cancer tryptophan500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1715863589528610.1002/cmdc.202200308