Paralog-dependent isogenic cell assay cascade generates highly selective SLC16A3 inhibitors.
Cell-based Assay
Chemical Probe
Chemical Proteomics
Chemical Screening
MCT4
SLC
SLC16
SLC16A3
Solute Carrier Transporters
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
17 08 2023
17 08 2023
Historique:
received:
27
01
2023
revised:
02
05
2023
accepted:
30
06
2023
medline:
21
8
2023
pubmed:
30
7
2023
entrez:
29
7
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37516113
pii: S2451-9456(23)00204-0
doi: 10.1016/j.chembiol.2023.06.029
pmc: PMC10437005
pii:
doi:
Substances chimiques
Carrier Proteins
0
Membrane Transport Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
953-964.e9Informations de copyright
Copyright © 2023 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences GmbH. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests V.D., A.C., and G.S.-F. are co-authors of patent applications related to presented study. S.K., G.E.W., and G.S.-F. are co-founders of company related to SLCs. G.S.-F. is the Academic Project Coordinator of the IMI RESOLUTE/Resolution consortium in partnership with Pfizer, Novartis, Bayer, Sanofi, Boehringer Ingelheim and Vifor Pharma. G.S.-F., G.E.W., and S.K. laboratories receive funds from Pfizer.
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