Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 133, Issue 2, Pages 96-102Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1016/j.jphs.2017.01.006
Keywords
L-type amino acid transporter 1 (LAT1); Inhibitor; Structure-activity relationship; Anti-cancer agent
Categories
Funding
- Japan Society for the Promotion of Science [15H04685]
- Ministry of Education, Culture, Sports, Science and Technology
- Grants-in-Aid for Scientific Research [15H04685, 16K19018] Funding Source: KAKEN
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L-type amino acid transporter 1 (LAT1) is known as a cancer-type amino acid transporter. In cancer cells, LAT1 is responsible for the cellular uptake of many essential amino acids including leucine that activates mechanistic/mammalian target of rapamycin (mTOR), regulating cancer cell growth. In this study, we designed a novel series of LAT1 inhibitors, SKN101e105, based on the structure of triiodothyronine (T3), a known LAT1 blocker. The compounds consist of core structure of 2-amino-3-[3,5-dichloro-4-(naphthalene-1-methoxy)-phenyl]-propanoic acid and different modifications on the naphthalene. Among them, the compounds including SKN103 with a modified phenyl group at C-7 position of naphthalene inhibited LAT1-mediated leucine transport, whereas SKN102 with a phenyl group at C-6 position did not, indicating the importance of the position of substituents on the naphthalene for the interaction with LAT1. SKN103 was suggested to be a non-transportable blocker rather than a substrate of LAT1 and inhibited LAT1 in a competitive manner with the K-i value of 2.1 mu M. SKN103 suppressed mTOR activity and the growth of cancer cells. Moreover, SKN103 in combination with cisplatin additively enhanced the growth inhibition in cancer cells. This study provides an additional insight into the structure-activity relationship of LAT1 ligands, which could lead to designing desirable LAT1 inhibitors. (C) 2017 The Authors.
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