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System L amino acid transporters are a member of the Solute Carrier transporter Family (SLC). L-Amino acid transporter 1 (LAT1) belong to SLC7 and requires the heavy chained 4F2hc chaperone protein for amino acid transport. LAT1 is expressed in tumor cells and cancerous cells in vivo are strongly linked to LAT1 expression. Herein, we provide historical aspects regarding initial Structure Activity Relationship (SAR) findings reported in 2002 with the oocyte model and in 2008 with S2-LAT1 and S2-LAT2 cell lines.  We summarize a series of dichloro- dibromo- and diiodo- tyrosine analogs that were prepared, and tested their potential to inhibit leucine transport in vitro to afford IC₅₀ values with a few being low microM LAT1 inhibitors.  We then summarize our efforts regarding novel LAT1 inhibitors with sub-nanomolar (nM) IC₅₀s to produce JPH203 which has completed Phase I clinical trial and is currently in Phase II trial in Japan. We describe differences observed between LAT1 and LAT2.  Overall, we provide an expanded SAR model regarding potent and selective LAT1 inhibitors.