Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics.
Journal
Nature biotechnology
ISSN: 1546-1696
Titre abrégé: Nat Biotechnol
Pays: United States
ID NLM: 9604648
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
22
08
2023
accepted:
25
03
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
aheadofprint
Résumé
Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose-response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. We found that histone deacetylase inhibitors potently and strongly down-regulated the T cell receptor complex resulting in impaired human T cell activation in vitro and ex vivo. This offers a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors.
Identifiants
pubmed: 38714896
doi: 10.1038/s41587-024-02218-y
pii: 10.1038/s41587-024-02218-y
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : FKZ161L0214A
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : FKZ031L0168
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : FKZ031L0168
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 325871075
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 325871075
Informations de copyright
© 2024. The Author(s).
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