title: Structure-activity relationship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1).
abstract: 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, SKN101-105, 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 Kivalue of 2.1 μM. 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.
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Pornparn
authors.initials: P
authors.lastname: Kongpracha
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.affiliation: Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Pattama
authors.initials: P
authors.lastname: Wiriyasermkul
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kaneda
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ohgaki
authors.affiliation: Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Electronic address: ykanai@pharma1.med.osaka-u.ac.jp.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000737:chemistry*; D007930:Leucine / Q000378:metabolism; D015394:Molecular Structure; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014284:Triiodothyronine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D027283:Large Neutral Amino Acid-Transporter 1; D014284:Triiodothyronine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D002945:Cisplatin
keywords: Anti-cancer agent; Inhibitor; L-type amino acid transporter 1 (LAT1); Structure-activity relationship