Discovery of Novel Aminobutanoic Acid-Based ASCT2 Inhibitors for the Treatment of Non-Small-Cell Lung Cancer

Abstract

Alanine-serine-cysteine transporter 2 (ASCT2) is up-regulated in lung cancers, and inhibiting it could potentially lead to nutrient deprivation, making it a viable strategy for cancer treatment. In this study, we present a series of ASCT2 inhibitors based on aminobutanoic acids, which exhibit potent inhibitory activity. Two compounds, <b>20k</b> and <b>25e</b>, were identified as novel and potent ASCT2 inhibitors, with IC₅₀ values at the micromolar level in both A549 and HEK293 cells, effectively blocking glutamine (Gln) uptake. Additionally, these compounds regulated amino acid metabolism, suppressed mTOR signaling, inhibited non-small-cell lung cancer (NSCLC) growth, and induced apoptosis. In vivo, experiments showed that <b>20k</b> and <b>25e</b> suppressed tumor growth in an A549 xenograft model, with tumor growth inhibition (TGI) values of 65 and 70% at 25 mg/kg, respectively, while <b>V9302</b> only achieved a TGI value of 29%. Furthermore, both compounds demonstrated promising therapeutic potential in patient-derived organoids. Therefore, these ASCT2 inhibitors based on aminobutanoic acids are promising therapeutic agents for treating NSCLC by targeting cancer Gln metabolism.