The L-type amino acid transporter 1 (LAT1, SLC7A5), a member of the solute carrier superfamily, transports dietary amino acids and amino acid drugs (<i>e.g.</i> gabapentin) into the brain. LAT1 is highly expressed at the blood-brain barrier (BBB) and on the surface of cancer cells. LAT1 could be targeted by inhibitors to treat cancer by decreasing the uptake of natural amino acids needed for cell signaling and metabolism or as a drug delivery route for amino acid prodrugs. Previously, we showed that δ-benzoyl L-ornithine was a modest inhibitor of LAT1 (54% inhibition at 200 μM). Guided by cryo-EM based models of the binding site, we synthesized a focused library of L-ornithine derivatives to test the effect of substituent size and functionality on potency. We will present the synthesis of these L-ornithine derivatives and SAR data from LAT1 cell assays. These findings could be useful for designing LAT1-targeted inhibitors for blocking cancer metabolism.

Synthesis and structure-activity relationship of L-ornithine derived inhibitors of the L-type amino acid transporter 1

ACS Fall 2021

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