Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors
- Author(s)
- 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, Stefan Kubicek, Giulio Superti-Furga
- 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.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Österreichische Akademie der Wissenschaften (ÖAW)
- Journal
- Cell Chemical Biology
- Volume
- 30
- Pages
- 953-964.e9
- ISSN
- 2451-9456
- DOI
- https://doi.org/10.1016/j.chembiol.2023.06.029
- Publication date
- 08-2023
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106013 Genetics
- Keywords
- ASJC Scopus subject areas
- Drug Discovery, Molecular Medicine, Molecular Biology, Biochemistry, Clinical Biochemistry, Pharmacology
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/paralogdependent-isogenic-cell-assay-cascade-generates-highly-selective-slc16a3-inhibitors(eb2c0978-d076-482d-b192-ebdb1fbbe6f2).html