How to develop amino acid transporter inhibitors (the good, the bad and the ugly)?

Amino acid transporters have developed into drugs targets for metabolic diseases, orphan diseases and cancer. This talk will present experiences with a variety of amino acid transport inhibitors. It will focus on methods to develop and validate amino acid transport inhibitors and possible pitfalls in lead compound development. This includes a variety of transport assays, structural and computational data.

References:
1.    Gauthier-Coles, G. et al. (2023) Do Amino Acid Antiporters Have Asymmetric Substrate Specificity? Biomolecules 13. 10.3390/biom13020301
2.    Gauthier-Coles, G. et al. (2022) Identification and characterization of a novel SNAT2 (SLC38A2) inhibitor reveals synergy with glucose transport inhibition in cancer cells. Front Pharmacol 13, 963066. 10.3389/fphar.2022.963066
3.    Yadav, A. et al. (2020) Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B(0)AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases. Front Pharmacol 11, 140. 10.3389/fphar.2020.00140
4.    Broer, A. et al. (2018) Disruption of Amino Acid Homeostasis by Novel ASCT2 Inhibitors Involves Multiple Targets. Front Pharmacol 9, 785. 10.3389/fphar.2018.00785
5.    Xu, J., Hu, Z., Dai, L. et al. Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19). Nat Commun 15, 7224 (2024). https://doi.org/10.1038/s41467-024-51748-1

Stefan Broer is Professor of Biochemistry at the Australian National University (ANU). He has more than 35 years of professional experience in the area of membrane biology working at the Research Center Jülich, the University of Illinois and the University of Tübingen before moving to the ANU in 2000. He has unique expertise in the areas of amino acid transport and amino acid homeostasis, which he has applied to identify and characterise novel transporter genes and to identify genes underlying rare genetic disorders. More recently, he has collaborated intensively with pharmaceutical industry to develop amino acid transporters as targets in metabolic diseases. Stefan Broer has developed and established numerous tools to investigate membrane transporters such as metabolomics, expression systems, protein biochemistry, electrophysiological recordings, high-throughput screening assays, mouse models, and human genetics.