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://ucrisportal.univie.ac.at/en/publications/paralogdependent-isogenic-cell-assay-cascade-generates-highly-selective-slc16a3-inhibitors(eb2c0978-d076-482d-b192-ebdb1fbbe6f2).html