nanvuranlat (JPH203) / J-Pharma, Ohara Pharma - LARVOL DELTA

Sustained reductions in valine and isoleucine mediate anti-cancer pharmacological effects of inhibiting amino acid transporter LAT1 in cancer cells. (PubMed, Cancer Metab) - "Reductions in valine and isoleucine in cancer cells primarily account for the multifaceted anti-cancer pharmacological activities of LAT1 inhibition by nanvuranlat. This study establishes the molecular basis for LAT1-targeted therapy and highlights growth-promoting processes in cancer cells that can be exploited pharmacologically by modulating the availability of specific amino acids."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • SLC7A5

Can the tumor microenvironment attenuate drug efficacy? Potential vulnerabilities of LAT1 inhibitors. (SNO 2025) - "The antitumor effects of nanvuranlat and JPH034 on glioma cells in vitro, are influenced by concentrations of essential amino acids and albumin. Specifically, amino acids decreased impact of the competitive inhibitor (nanvuranlat) while albumin decreased impact of the non-competitive inhibitor (JPH034). These results suggest that the composition of the tumor microenvironment, which is impacted by BBB-disruption within GBM may differentially attenuate the therapeutic efficacy of certain drugs including LAT1 inhibitors."

Biomarker • Clinical • Tumor microenvironment • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Targeting Amino Acid Transporter in Malignant Peripheral Nerve Sheath Tumors: A Strategy to Enhance Efficacy of Chemotherapy and Targeted Therapy (SNO 2025) - "JPH203 induced dose-dependent growth inhibition in multiple MPNST cell lines (IC₅₀: 10-30 µM) and reduced phosphorylated p70S6 levels in a dose- and time-dependent manner, indicating mTORC1 pathway suppression. Combination treatment with LAT1 inhibitor and doxorubicin enhanced cytotoxicity compared to monotherapy... These findings support LAT1 inhibition as a promising therapeutic strategy in MPNST. Synergy with chemotherapy and targeted agents such as MEK inhibitors highlights the potential to exploit metabolic vulnerabilities and enhance the efficacy of existing treatment regimens in this challenging sarcoma subtype."

Clinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • SLC7A5

Targeting Amino Acid Transporter in Malignant Peripheral Nerve Sheath Tumors: A Strategy to Enhance Efficacy of Chemotherapy and Targeted Therapy (WFNOS 2025) - "JPH203 induced dose-dependent growth inhibition in multiple MPNST cell lines (IC₅₀: 10-30 µM) and reduced phosphorylated p70S6 levels in a dose- and time-dependent manner, indicating mTORC1 pathway suppression. Combination treatment with LAT1 inhibitor and doxorubicin enhanced cytotoxicity compared to monotherapy... These findings support LAT1 inhibition as a promising therapeutic strategy in MPNST. Synergy with chemotherapy and targeted agents such as MEK inhibitors highlights the potential to exploit metabolic vulnerabilities and enhance the efficacy of existing treatment regimens in this challenging sarcoma subtype."

Clinical • Brain Cancer • Neurofibrosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • SLC7A5

Treatment with L-type amino acid transporter 1 inhibitor JPH203 enhances protein synthesis in C2C12 myotubes. (PubMed, Sci Rep) - "ATP-competitive mTOR inhibitor AZD8055 (1 μM) suppressed JPH203-induced protein synthesis. JPH203 treatment increased intracellular glutamine concentration. These results suggest that inhibition of LAT1 function augments muscle protein synthesis, possibly through the activation of rapamycin-insensitive mTOR signaling; elevated intracellular glutamine levels may contribute to the enhancement of muscle protein synthesis induced by LAT1 inhibition."

Journal • EIF4EBP1

Can the tumor microenvironment attenuate drug efficacy? Potential vulnerabilities of LAT1 inhibitors. (WFNOS 2025) - "The antitumor effects of nanvuranlat and JPH034 on glioma cells in vitro, are influenced by concentrations of essential amino acids and albumin. Specifically, amino acids decreased impact of the competitive inhibitor (nanvuranlat) while albumin decreased impact of the non-competitive inhibitor (JPH034). These results suggest that the composition of the tumor microenvironment, which is impacted by BBB-disruption within GBM may differentially attenuate the therapeutic efficacy of certain drugs including LAT1 inhibitors."

Biomarker • Clinical • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor

Subgroup analysis of a phase II study of nanvuranlat in pre-treated, advanced, refractory biliary tract cancer patients (BTC) support an enriched patient population for a planned phase III study (ESMO 2025) - "Further, patients without the prior-primary resection also demonstrated favourable OS HR: 0.53 [95% CI: 0.28, 1.01]), as well as patients who had only received a first-line treatment may benefit from treatment with nanvuranlat (OS HR = 0.55, [95% CI: 0.09, 3.53]). Table: 98P Subgroup N HR (95% CI) Primary tumour site Intrahepatic bile duct 27 0.67 (0.33 – 1.36) Extrahepatic bile duct 15 1.13 (0.39 – 3.25) Gallbladder 16 0.69 (0.26 – 1.78) Ampula of Vater 11 1.92 (0.52 – 7.10) IHC/EHC/GBC 58 0.76 (0.46 – 1.26) Treatment line 2nd 12 0.55 (0.09 – 3.53) 3rd 30 1.24 (0.56 – 2.73) > 4th 27 0.77 (0.35 – 1.66) Prior primary resection Yes 36 1.41 (0.72 – 2.76) No 33 0.53 (0.28 – 1.01) Conclusions This subgroup analysis indicates that the efficacy of nanvuranlat in OS may be enhanced in IHC/EHC/GBC patients who had no prior resection and received only a first-line treatment."

Clinical • Metastases • P2 data • P3 data • Biliary Cancer • Biliary Tract Cancer • Gallbladder Cancer • Oncology • Solid Tumor

Screening for novel L-type amino acid transporter 1 (SLC7A5) inhibitors using a fluorescent amino acid. (PubMed, Biochem Biophys Res Commun) - "L-type amino acid transporter 1 (LAT1) facilitates the transport of neutral amino acids with bulky side chains, including many essential amino acids that activate the mechanistic target of rapamycin (mTOR), thereby promoting cell proliferation...The transport of H-Ala (2-Acd)-OH・HCl was inhibited by the LAT1-specific inhibitor JPH203 and by excess leucine, a natural LAT1 substrate. In contrast, the structurally similar fluorescent amino acid (S)-2-Amino-3-(12-oxo-5,12-dihydrobenzo [b] acridin-2-yl) propanoic acid hydrochloride (H-Ala (2-Bacd)-OH・HCl) exhibited minimal cellular uptake. Using H-Ala (2-Acd)-OH・HCl and Ca9-22 cells, we screened over 10,000 compounds and identified several potent LAT1 inhibitors."

Journal • Genetic Disorders • Nephrology • Oncology • Polycystic Kidney Disease • Renal Disease • CA9 • mTOR • SLC7A5

A Novel Approach for Cisplatin-Resistant Esophageal Squamous Cell Carcinoma via Amino Acid Transporter LAT1 Inhibition. (PubMed, Cancer Med) - "LAT1 contributes to cisplatin resistance in ESCC by sustaining amino acid metabolism and promoting mTOR-dependent autophagy. Targeting LAT1 with JPH203 enhances cisplatin sensitivity, suggesting that LAT1 inhibition could be a promising therapeutic strategy for overcoming chemoresistance in ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

JPH203 alleviates renal fibrosis via inhibition of serine-related mTORC1 pathway in TGF-β1-induced fibroblasts and UUO mice. (PubMed, Exp Cell Res) - "In conclusion, our study demonstrated that JPH203 can alleviate renal fibrosis via inhibition of serine-related mTORC1 pathway in fibroblasts in UUO mice. These results may provide a theoretical foundation for the pathogenesis of renal fibrosis and a novel therapeutic strategy for CKD."

Journal • Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • ATF4 • PHGDH • SLC7A5 • TCF4 • TGFB1 • VIM

Pharmacodynamic analyses of LAT1 inhibitors in vitro and in vivo by targeted metabolomics reveal target-independent effects. (PubMed, Biomed Pharmacother) - "We generated and characterized LAT1- and LAT2-expressing cells using the human MDST8 cell line lacking these transporters to evaluate the specificity and selectivity of the clinical candidate JPH203 and novel LAT1 inhibitors...This study demonstrates the utility of employing targeted metabolomics to interrogate LAT1/2 inhibitor selectivity in different physiological matrices in vitro, ex vivo and in vivo. Overall, our findings reveal LAT1-dependent and previously unrecognized LAT-independent effects of inhibitors believed to act specifically on LAT1."

Journal • PK/PD data • Preclinical • Oncology • SLC3A2 • SLC7A5

Amino acid transporter LAT1 (SLC7A5) promotes metabolic rewiring in TNBC progression through the L-Trp/QPRT/NAD+ pathway. (PubMed, J Exp Clin Cancer Res) - "These findings identify a novel role of LAT1 in promoting TNBC progression and chemo-resistance by amplifying the Warburg effect, positioning LAT1 as a promising therapeutic target for TNBC treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • LDHA • PKM • QPRT • SLC7A5

Study on dissociated states of twenty proteinogenic amino acids and their interactions with LAT1 by HPCE-IICRD. (PubMed, J Chromatogr A) - "Besides, competitive binding experiments proved that JPH203 (LAT1-specific inhibitor) and leucine shared the same binding site. HPCE-IICRD provides a new method to reveal the interaction between different dissociated forms of AAs or other biomolecules and essential receptors."

Journal

Targeting LAT1 with JPH203 to reduce TNBC proliferation and reshape suppressive immune microenvironment by blocking essential amino acid uptake. (PubMed, Amino Acids) - "This study highlights the therapeutic potential of targeting LAT1 in TNBC, particularly in remodeling the tumor immune microenvironment. The findings provide a promising strategy for immune combination therapy in TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Multiplex Methionine Modulating Hydrogel for Cancer Metabolic Therapy. (PubMed, Adv Mater) - "Small molecule inhibitors PF9366 and adenosine dialdehyde are encapsulated by tumor cell-targeting nanoparticles (NPs) to achieve a cascaded blockage of intracellular methionine metabolism. These NPs are further co-loaded with the extracellular methionine uptake inhibitor JPH203 into a type of reactive oxygen species-sensitive hydrogel, assembling the multiplex methionine modulating hydrogel (3 M Gel)...Moreover, remodeling of the tumor microenvironment by 3 M Gel overcomes immune checkpoint blockade resistance in TNBC. This study presents a localized triple regulation strategy and paves a new path for amino acid starvation-based cancer therapy."

Journal • Breast Cancer • Colorectal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Structural basis of anticancer drug recognition and amino acid transport by LAT1. (PubMed, Nat Commun) - "JPH203 (also known as nanvuranlat or KYT-0353), an anticancer drug in clinical trials, traps LAT1 in an outward-facing state with a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3) and bending TM10. Physiological substrates like ʟ-Phe lack such effects, whereas melphalan poses steric hindrance, explaining its inhibitory activity. The "classical" system L inhibitor BCH induces an occluded state critical for transport, confirming its substrate-like behavior. These findings provide a structural basis for substrate recognition and inhibition of LAT1, guiding future drug design."

Journal • Oncology • SLC7A5

Pharmacological and structural insights into nanvuranlat, a selective LAT1 (SLC7A5) inhibitor, and its N-acetyl metabolite with implications for cancer therapy. (PubMed, Sci Rep) - "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."

Journal • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • SLC7A5

Negative regulation of thyroid adenoma-associated protein (THADA) in the cardiac glycoside-induced anti-cancer effect. (PubMed, J Physiol Sci) - "Three kinds of cardiac glycosides (ouabain, oleandrin, and digoxin) inhibited the cancer cell proliferation and decreased the expression level of thyroid adenoma-associated protein (THADA). The LAT1 inhibitor, JPH203, significantly weakened the cancer cell proliferation. These results suggest that the binding of cardiac glycosides to Na+,K+-ATPase negatively regulates the THADA-LAT1 pathway, exerting the anti-proliferative effect in cancer cells."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Thyroid Gland Carcinoma

Extrajunctional CLDN10 cooperates with LAT1 and accelerates clear cell renal cell carcinoma progression. (PubMed, Cell Commun Signal) - "We conclude that CLDN10-LAT1 signaling drives ccRCC progression. Taken together with our previous findings on CLDN-Src-family kinases signaling, CLDNs propagate distinct intracellular signals depending on their association with different binding partners."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

JPH203 alleviates peritoneal fibrosis via inhibition of amino acid-mediated mTORC1 signaling. (PubMed, Biochem Biophys Res Commun) - "JPH203 alleviates PF by inhibiting amino acid-mediated mTORC1 signaling."

Journal • Fibrosis • Immunology • TGFB1

LAT1 supports mitotic progression through Golgi unlinking in an amino acid transport activity-independent manner. (PubMed, J Biol Chem) - "Unexpectedly, JPH203, an inhibitor of LAT1 amino acid transport activity, does not affect mitotic progression...These results suggest that LAT1 supports mitotic progression in an amino acid transport activity-independent manner and that Golgi-localized LAT1 is important for mitotic progression through the acceleration of Golgi unlinking and centrosome maturation. These findings reveal a novel LAT1 function in mitosis."

Journal • Oncology • SLC3A2 • SLC7A5

Endothelial specific LAT1 ablation normalizes tumor vasculature. (PubMed, JCI Insight) - "TNFα-induced expression of VCAM1 and E-selectin at the surface of HUVEC, both of which are responsible for enhanced monocyte attachment and pre-metastatic niche formation, was reduced in the presence of LAT1 inhibitor, nanvuranlat. Deprivation of tryptophan, an LAT1 substrate, mimicked LAT1 inhibition, which led to activation of MEK1/2-ERK1/2 pathway and subsequent cystathionine γ lyase (CTH) induction. Increased production of hydrogen sulfide (H2S) by CTH was at least partially responsible for tumor vascular normalization, leading to decreased leakiness and enhanced delivery of chemotherapeutic agents to the tumor."

Journal • Oncology • CDH5 • MAP2K1 • SLC7A5 • TNFA • VCAM1

Phase II Placebo-Controlled Study of the Effect and Safety of Nanvuranlat in Patients with Advanced Biliary Tract Cancers Previously Treated by Systemic Chemotherapy. (PubMed, Clin Cancer Res) - "Compared with placebo, nanvuranlat improved PFS in patients with advanced and refractory BTC with an acceptable safety profile. Further studies of this promising compound are warranted in the population of patients who are exhausted from treatment options."

Clinical • Journal • Metastases • P2 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

Structural basis for the inhibition mechanism of LAT1-4F2hc complex by JPH203. (PubMed, Cell Discov) - No abstract available

Journal • SLC3A2

PLGA nanoparticles targeted loading LAT1 inhibitor JPH203 for targeted regulation of amino acid metabolism for ulcerative colitis (AOCC 2024) - No abstract available

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis