LAT1 (SLC7A5) is an L-type amino acid transporter that transports branched hydrophobic and aromatic amino acids, including L-Tyr and L-Trp, across the cell membrane in exchange for glutamine. The expression of LAT1 is restricted to endothelial cells of tissue barriers, such as the blood-brain barrier, the placenta, and the spleen. At the same time, the transporter is overexpressed in a variety of human cancers, which makes LAT1 an attractive target for new types of anticancer drugs that would be distinct from conventional cytotoxics, signal transduction inhibitors or epigenetic modulators. In this contribution, we discuss the exploration of conformationally restricted derivatives of O-benzyl-meta-l-Tyr (1) and 5-benzyloxy-L-Trp (2) as new LAT1 inhibitors. Amino acids 1 and 2 had been identified as inhibitors of radioactive l-Leu uptake into HT-29 colon carcinoma cells with IC50 values of 9 μM and 19 μM, respectively. Linking the α-carbon in 1 or 2 to the aromatic ring via a CH2-linkage together with appropriate modifications of the benzyloxy substituents led to the identification of sub-micromolar inhibitors of LAT1-mediated transport of l-Leu. The best compounds were at least equipotent with the Phase II compound JPH203. For several of the meta-l-tyrosine derived inhibitors, cryo-electron microscopy structures were obtained for the corresponding complexes with LAT1, showing the transporter in an outward-open conformation. The implications of these structural findings for the mechanism of transport by LAT1 will also be discussed.

Conformationally restricted derivatives of L-tyrosine and L-tryptophan as inhibitors of the L-type amino acid transporter LAT1

ACS Spring 2022

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