Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy
Year: 2025
Type: article
Abstract: L-type amino acid transporter 1 (LAT1, SLC7A5), overexpressed in various cancers, mediates the uptake of essential amino acids crucial for tumor growth. It has emerged as a promising target for cancer therapy. Nanvuranlat (JPH203/KYT-0353), a LAT1 inhibitor, has shown antitumor activity in preclinical studies and efficacy in biliary tract cancer during clinical trials. This study provides a comprehensive pharmacological characterization of nanvuranlat and its N -acetyl metabolite, including structural insights into their LAT1 interactions. Both compounds demonstrated high selectivity for LAT1 over LAT2 and other amino acid transporters. Nanvuranlat acts as a competitive, non-transportable LAT1 inhibitor ( K i = 38.7 nM), while its N -acetyl metabolite retains selectivity but with reduced affinity ( K i = 1.68 µM). Nanvuranlat exhibited a sustained inhibitory effect on LAT1 even after its removal, indicating the potential for prolonged therapeutic effects. Both compounds showed comparable dissociation rates, suggesting that N -acetylation does not affect the interaction responsible for slow dissociation. The U-shaped conformation adopted by nanvuranlat when bound to LAT1 likely contributes to its high affinity, selectivity, sustained inhibitory effect, and non-transportable nature observed in this study. These insights into nanvuranlat’s mechanism and metabolic impact provide essential information for understanding its clinical efficacy and advancing LAT1-targeted cancer therapies.
Source: Scientific Reports
Institution: The University of Osaka
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,690
Awards: Structural and Pharmacological Basis of Residence Time / Sustained Inhibition of Amino Acid Transporter Inhibitors, Study on the amino acid signaling via transporters and receptors for the pharmacologic control of cellular metabolism, Elucidation of the transmembrane signal mechanism responsible for metabolic control by amino acid availability, Collaborative function of amino acid transporter LAT1 and VEGF-A in tumor angiogenesis, G5704117428, Mechanistic analysis of potent cell cycle control and dormancy induction by amino acid transporter inhibitors in cancer cells
OpenAlex ID: W4406776980