Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors

01.08.2023

The solute carrier (SLC) superfamily of membrane transporters plays an important role in cellular homeostasis and metabolism. An increasing number of SLCs is being linked to different human diseases, which is reflected in a growing interest in SLC-oriented drug discovery. Yet if compared with other protein families, the SLC superfamily remains pharmacologically underexploited. This originates on one hand from the fact that most SLCs are relatively understudied and on the other hand from a lack of tools, such as chemicals targeting SLC function or appropriate biological assays.

Vojtech Dvorak, Andrea Casiraghi, Claire Colas, Anna Koren, Tatjana Tomek, Fabian Offensperger, Andrea Rukavina, Gary Tin, Elisa Hahn, Sarah Dobner, Fabian Frommelt, Andras Boeszoermenyi, Viktoriia Bernada, J. Thomas Hannich, Gerhard F. Ecker, Georg E. Winter et al., Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors. Cell Chemical Biology 2023, 30, 1–12

DOI

https://doi.org/10.1016/j.chembiol.2023.06.029

Abstract

Despite being considered druggable and attractive therapeutic targets, most of the solute carrier (SLC) membrane transporters remain pharmacologically underexploited. One of the reasons for this is a lack of reliable chemical screening assays, made difficult by functional redundancies among SLCs. In this study we leveraged synthetic lethality between the lactate transporters SLC16A1 and SLC16A3 in a screening strategy that we call paralog-dependent isogenic cell assay (PARADISO). The system involves five isogenic cell lines, each dependent on various paralog genes for survival/fitness, arranged in a screening cascade tuned for the identification of SLC16A3 inhibitors. We screened a diversity-oriented library of ∼90,000 compounds and further developed our hits into slCeMM1, a paralog-selective and potent SLC16A3 inhibitor. By implementing chemoproteomics, we showed that slCeMM1 is selective also at the proteome-wide level, thus fulfilling an important criterion for chemical probes. This study represents a framework for the development of specific cell-based drug discovery assays.

Rights & permissions

This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2023 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences GmbH. Published by Elsevier Ltd.

Keywords

Solute Carrier Transporters; SLC; Chemical Screening; Cell-based Assay; SLC16; SLC16A3; MCT4; Chemical Probe; Chemical Proteomics

© 2023 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences GmbH. Published by Elsevier Ltd.

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