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Decrypting the molecular basis of cellular drug phenotypes by dose-resolved expression proteomics

ABSTRACT: 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 which informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in >1 million dose-response curves that can be interactively explored online in ProteomicsDB and a custom-built ShinyApp. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered novel aspects of the MoAs of human medicines. Most notable, HDAC inhibitors potently and strongly down-regulated the T-cell receptor complex resulting in impaired human T-cell activation in-vitro and ex-vivo. This not only offers a rational explanation for the efficacy of HDAC inhibitors in certain lymphomas and autoimmune diseases but also their poor performance in treating solid tumors.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Exploris 480

ORGANISM(S): Pseudomonas Aeruginosa (ncbitaxon:287) Arabidopsis Thaliana (ncbitaxon:3702) Escherichia Coli (ncbitaxon:562) Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Bernhard Kuster

PROVIDER: MSV000093659 | MassIVE | Wed Dec 13 12:34:00 GMT 2023

SECONDARY ACCESSION(S): PXD047799

REPOSITORIES: MassIVE

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