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

P1, N=12, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jun 2025 --> Jun 2026

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.

P3, N=50, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Not yet recruiting --> Recruiting

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.

P3, N=18, Not yet recruiting, Telix Pharmaceuticals

P3, N=50, Not yet recruiting, Telix Pharmaceuticals (Innovations) Pty Limited

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.