Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy
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...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87522-6 |
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| author | Chunhuan Jin Xinyu Zhou Minhui Xu Hiroki Okanishi Ryuichi Ohgaki Yoshikatsu Kanai |
| author_facet | Chunhuan Jin Xinyu Zhou Minhui Xu Hiroki Okanishi Ryuichi Ohgaki Yoshikatsu Kanai |
| author_sort | Chunhuan Jin |
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| description | 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. |
| format | Article |
| id | doaj-art-c4d25c7097a94328abbb8a0746a81586 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-c4d25c7097a94328abbb8a0746a815862025-01-26T12:31:31ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-025-87522-6Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapyChunhuan Jin0Xinyu Zhou1Minhui Xu2Hiroki Okanishi3Ryuichi Ohgaki4Yoshikatsu Kanai5Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityDepartment of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityDepartment of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityDepartment of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityDepartment of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityDepartment of Bio-System Pharmacology, Graduate School of Medicine, Osaka UniversityAbstract 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.https://doi.org/10.1038/s41598-025-87522-6Amino acid transporterLAT1 inhibitorPharmacological selectivityDrug metabolism & efficacyCancer therapy |
| spellingShingle | Chunhuan Jin Xinyu Zhou Minhui Xu Hiroki Okanishi Ryuichi Ohgaki Yoshikatsu Kanai Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy Scientific Reports Amino acid transporter LAT1 inhibitor Pharmacological selectivity Drug metabolism & efficacy Cancer therapy |
| title | Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy |
| title_full | Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy |
| title_fullStr | Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy |
| title_full_unstemmed | Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy |
| title_short | Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy |
| title_sort | pharmacological and structural insights into nanvuranlat a selective lat1 slc7a5 inhibitor and its n acetyl metabolite with implications for cancer therapy |
| topic | Amino acid transporter LAT1 inhibitor Pharmacological selectivity Drug metabolism & efficacy Cancer therapy |
| url | https://doi.org/10.1038/s41598-025-87522-6 |
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