A versatile acoustic droplet ejection mass spectrometry platform enables drug discovery for the solute carrier (SLC) target family

Acoustic ejection mass spectrometry has emerged as a powerful bioanalytical tool by combining the precision and accuracy of mass spectrometry with the speed provided by acoustic dispensing technology. Based on the variety of analytes that can be quantified with this method, we asked whether it could cover the range of pharmacologically relevant molecules transported by members of the solute carrier protein family and potentially become a universal assay principle for this class of drug targets. Here, we report the establishment of a high-throughput compatible assay platform based on acoustic ejection mass spectrometry that enables quantification of a variety of SLC substrates. As proof-of-concept, we set up cell-based assays for transporters belonging to several SLC sub-families, and used key optimization parameters, to assess method development steps deemed critical for successful application of the technology. Finally, we demonstrate its scalability for hit identification purposes, by performing a pilot HTS campaign for SGLT2, a prominent drug target among the members of the SLC family. Our study redefines the landscape of enabling technologies for SLCs, offering a powerful and versatile toolbox for the identification and mechanistic characterization of SLC modulators.