A Selective and Slowly Reversible Inhibitor of l‑Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells

The l-type
amino acid transporter 1 (LAT1) is a transmembrane
protein carrying bulky and neutral amino acids into cells. LAT1 is
overexpressed in several types of tumors, and its inhibition can result
in reduced cancer cell growth. However, known LAT1 inhibitors lack
selectivity over other transporters. In the present study, we designed
and synthesized a novel selective LAT1 inhibitor (1),
which inhibited the uptake of LAT1 substrate, l-leucin as
well as cell growth. It also significantly potentiated the efficacy
of bestatin and cisplatin even at low concentrations (25 μM).
Inhibition was slowly reversible, as the inhibitor was able to be
detached from the cell surface and blood–brain barrier. Moreover,
the inhibitor was metabolically stable and selective toward LAT1.
Since the inhibitor was readily accumulated into the prostate after
intraperitoneal injection to the healthy mice, this compound may be
a promising agent or adjuvant especially for the treatment of prostate
cancer.