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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Discovery of Novel Aminobutanoic Acid-Based ASCT2 Inhibitors for the Treatment of Non-Small-Cell Lung Cancer
Lian Qin1, Xinying Cheng1, Shijiao Wang2
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211100, P. R. China.
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, 20k and 25e, 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 20k and 25e suppressed tumor growth in an A549 xenograft model, with tumor growth inhibition (TGI) values of 65 and 70% at 25 mg/kg, respectively, while V9302 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.
Insights
Novel aminobutanoic acid compounds effectively inhibit the alanine-serine-cysteine transporter 2 (ASCT2), a key target in lung cancer. These inhibitors block glutamine uptake, suppress tumor growth, and show therapeutic promise for non-small-cell lung cancer (NSCLC).
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Alanine-serine-cysteine transporter 2 (ASCT2) is upregulated in lung cancers.
- Inhibiting ASCT2 offers a potential strategy for cancer treatment via nutrient deprivation.
Purpose of the Study:
- To develop and evaluate novel ASCT2 inhibitors based on aminobutanoic acids.
- To assess the efficacy of these inhibitors in preclinical models of non-small-cell lung cancer (NSCLC).
Main Methods:
- Synthesis and characterization of aminobutanoic acid-based ASCT2 inhibitors.
- In vitro assays to determine inhibitory activity (IC50) and effects on glutamine uptake.
- Assessment of effects on amino acid metabolism, mTOR signaling, and apoptosis in cancer cells.
- In vivo studies using A549 xenograft models and evaluation in patient-derived organoids.
Main Results:
- Compounds 20k and 25e demonstrated potent ASCT2 inhibition with micromolar IC50 values in A549 and HEK293 cells.
- These inhibitors effectively blocked glutamine uptake, regulated amino acid metabolism, suppressed mTOR signaling, and induced apoptosis.
- In vivo, 20k and 25e significantly suppressed tumor growth in an A549 xenograft model, showing higher tumor growth inhibition (TGI) than V9302.
- Promising therapeutic potential was observed in patient-derived organoids.
Conclusions:
- Aminobutanoic acid-based ASCT2 inhibitors are effective in blocking cancer cell glutamine metabolism.
- Compounds 20k and 25e represent promising therapeutic agents for NSCLC treatment.
- Targeting ASCT2 and cancer glutamine metabolism is a viable strategy for NSCLC therapy.
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