ArticleProceedings of the National Academy of Sciences of the United States of America2021
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 61 citations in OpenAlex.
- ESMDynamic: Fast and accurate prediction of protein dynamic contact maps from single sequences.Nature communications · 2026Article
- Modeling the Sensitivity of Large-Scale Virtual Screening to Scoring Function Accuracy, Artifacts, and Library Composition.Journal of chemical information and modeling · 2026Article
- Selection of short Gadd45β-binding peptides through a synergistic computational and biophysical approach.Protein science : a publication of the Protein Society · 2025Article
- Modeling cryo-EM structures in alternative states with AlphaFold2-based models and density-guided simulations.Communications chemistry · 2025Article
- Modeling protein conformational ensembles by guiding AlphaFold2 with Double Electron Electron Resonance (DEER) distance distributions.Nature communications · 2025Article
- Recent advances in ASCT2 inhibitors: ligand design and therapeutic applications.Future medicinal chemistry · 2025Review
- Ensemble refinement of mismodeled cryo-EM RNA structures using all-atom simulations.Nature communications · 2025Article
- Easy and accurate protein structure prediction using ColabFold.Nature protocols · 2025Review
- Targeting emerging amino acid dependencies and transporters in cancer therapy.Frontiers in pharmacology · 2025Review
- Receptor-recognition and antiviral mechanisms of retrovirus-derived human proteins.Nature structural & molecular biology · 2024Article
- Accurate model and ensemble refinement using cryo-electron microscopy maps and Bayesian inference.PLoS computational biology · 2024Article
- Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2).Molecules (Basel, Switzerland) · 2024Article
- Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches.Pharmaceutics · 2024Review
- Cryo-electron microscopy-based drug design.Frontiers in molecular biosciences · 2024Review
- Circular RNA in Non-small Cell Lung Carcinoma: Identification of Targets and New Treatment Modalities.Cancer genomics & proteomics · 2023Review
- Article
- Targeting SLC transporters: small molecules as modulators and therapeutic opportunities.Trends in biochemical sciences · 2023Review
- Determination of the Structure and Dynamics of the Fuzzy Coat of an Amyloid Fibril of IAPP Using Cryo-Electron Microscopy.Biochemistry · 2023Article
- SLC1A5, unrelated to prognosis, was associated with CD8Heliyon · 2023Article
- Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.