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

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

AMINO ACID INFLUX VIA LAT1 REGULATES IRON DEPENDENCY OF AGGRESSIVE NATURAL KILLER CELL LEUKEMIA (EHA 2024) - "Taken together, we discovered that the amount of extracellular sulfur amino acid influx through LAT1 was thekey environmental factor determining the iron dependency of ANKL cells, which provides a good explanationfor the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoidcontains abundant amino acids absorbed from the gut."

Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • SLC7A5

Targeting the Amino Acid Transporter SLC7A5 for Pulmonary Fibrosis (ATS 2024) - "The preclinical efficacy of JPH203 was evaluated in murine bleomycin treatment model of pulmonary fibrosis. In summary, our results have revealed a novel molecular and metabolic pathway(s) modulating fibrosis resolution and would be a promising cell selective therapy for IPF targeting cellular metabolism. Research Funding: NHLBI (R56HL158549 and R01HL167732 for M. C)"

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • MYC • SLC7A5 • TGFB1

Amino acid transport inhibition resensitizes enzalutamide-resistant prostate cancer cells to enzalutamide (AUA 2024) - "We treated enzalutamide-sensitive and -resistant PCa cells with varying concentrations of amino acid transport inhibitors JPH203 or V9302 either singly or in combination with enzalutamide and assessed cell survival, cell viability, proliferation, and survival in 3-D models. Our results indicate that increasing amino acid import may be one of the metabolic mechanisms employed by PCa cells during the acquisition of resistance to enzalutamide. These results imply that inhibiting elevated amino acid import into cancer cells may be an attractive modality to overcome enzalutamide resistance."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR

The role of CD98 heavy chain in cancer development. (PubMed, Histol Histopathol) - "In colorectal cancer, CD98hc emerges as a potential therapeutic target, along with its partner LAT1, and inhibitors like JPH203 exhibit promise in preclinical studies. Targeting CD98hc/LAT1, alone or with conventional therapies, shows promise in inhibiting tumor growth. This review focuses on elucidating the multifaceted roles of CD98hc and its partner LAT1 in cancer, particularly its involvement in amino acid transport, signaling pathways, and its prognostic relevance in cancer."

Journal • Review • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • SLC3A2 • SLC7A5

Comparative study of susceptibility to methylmercury cytotoxicity in cell types composing rat peripheral nerves: a higher susceptibility of dorsal root ganglion neurons. (PubMed, J Toxicol Sci) - "Additionally, decreased cell viability caused by methylmercury was significantly reduced by either the LAT1 inhibitor, JPH203, or siRNA-mediated knockdown of LAT1. On the other hand, an MRP2 inhibitor, MK571, significantly intensified the decrease in the cell viability caused by methylmercury. Our results provide a cellular basis for sensory neve predominant injury in the peripheral nerves of Minamata disease patients."

Clinical • Journal • Preclinical • Pain

The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism. (PubMed, Cancer Sci) - "Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD24

Opsonization Inveigles Macrophages Engulfing Carrier-Free Bilirubin/JPH203 Nanoparticles to Suppress Inflammation for Osteoarthritis Therapy. (PubMed, Adv Sci (Weinh)) - "Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

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

Upregulation of ATF4 mediates the cellular adaptation to pharmacologic inhibition of amino acid transporter LAT1 in pancreatic ductal adenocarcinoma cells. (PubMed, J Pharmacol Sci) - "This study examined the adaptive response to LAT1 inhibition using nanvuranlat, a high-affinity LAT1 inhibitor...Importantly, dual targeting of LAT1 and ATF4 exhibited more substantial anti-proliferative effects in vitro than individual treatments. This study underscores the potential of combining LAT1 and ATF4 inhibition as a therapeutic strategy in cancer treatment."

Journal • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • ATF4

Inhibition of amino acid transporter LAT1 in cancer cells suppresses G0/G1-S transition by downregulating cyclin D1 via p38 MAPK activation. (PubMed, J Pharmacol Sci) - "Nanvuranlat (Nanv; JPH203, KYT-0353), a selective LAT1 inhibitor, suppresses the uptake of large neutral amino acids required for rapid growth and proliferation of cancer cells...The increased phosphorylation of p38 MAPK and the decrease of cyclin D1 were recapitulated in xenograft tumor models treated with Nanv. This study contributes to delineating the pharmacological activities of LAT1 inhibitors as anti-cancer agents and provides significant insights into the molecular basis of the amino acid-dependent cell cycle checkpoint at G0/G1 phase."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CCND1 • SLC7A5

Treatment outcomes by stratifying the N-acetyl transferase 2 phenotype in pre-treated patients with advanced refractory biliary tract cancer treated with nanvuranlat, an L-type amino acid transporter inhibitor: An ad-hoc analysis of a randomized, double-blind, placebo-controlled phase 2 study. (ASCO-GI 2024) - "By classifying BTC patients by NAT2 phenotype in this ad hoc analysis, the LAT1 inhibitor nanvuranlat further improved its clinical efficacy and safety in the NAT2 NR population. Therefore, selecting NAT2 NR for nanvuranlat treatment may improve the risk -benefit ratio. Clinical trial information: UMIN000034080."

Clinical • Metastases • P2 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • NAT2 • SLC7A5

L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity. (PubMed, Cancer Sci) - "Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SLC7A5