nanvuranlat (JPH203)

P3, N=480, Recruiting, J-Pharma Co., Ltd. | Not yet recruiting --> Recruiting

Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.

P3, N=480, Not yet recruiting, J-Pharma Co., Ltd.

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.

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.

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.

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.

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.

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.

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.

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.