The emerging field of chemo‐ and pharmacoproteomics

Abstract

The emerging field of chemo- and pharmacoproteomics studies the mechanisms of action of bioactive molecules in a systems pharmacology context. In contrast to traditional drug discovery, pharmacoproteomics integrates the mechanism of a drug's action, its side effects including toxicity, and the discovery of new drug targets in a single approach. Thus, it determines early favorable (e.g. multiple kinase target in cancer drugs) and unfavorable (e.g. side effects) polypharmacology. Target profiling is accomplished using either active site-labeling probes or immobilized drugs. This strategy identifies direct targets and has in fact enabled even the determination of binding curves and half maximum inhibitory concentrations of these targets. In addition, the enrichment greatly reduces the complexity of the proteome to be analyzed by quantitative MS. Complementary to these approaches, global proteomics profiling studying drug treatement-induced changes in protein expression levels and/or post-translational modification status have started to become possible mostly due to significant improvements in instrumentation. Particularly, when using multidimensional separations, a considerable proteome depth of up to 10 000 proteins can be achieved with current state-of-the-art mass spectrometers and bioinformatics tools. In summary, chemo- and pharmacoproteomics has already contributed significantly to the identification of novel drug targets and their mechanisms of action(s). Aided by further technological advancements, this interdisciplinary approach will likely be used more broadly in the future.

Translational biomarkers of acetaminophen-induced acute liver injury

“…The omics technologies have provided scientists with the ability to better characterize the phenotypes of patients and to discover biomarkers of diseases (Wood et al 2014 ). When omics studies are applied to define an individual’s response to drugs, they are often referred to as pharmacogenomics, pharmacoproteomics and pharmacometabonomics or pharamacometabolomics, (Clayton et al 2006 ; Everett et al 2013 ; Hess 2013 ; Kaddurah-Daouk and Weinshilboum 2014 ; Lindpaintner 2002 ; Nicholson et al 2011 ). In contrast, when the omics platforms are applied in toxicity studies, they are often referred to as toxicogenomics, toxicoproteomics and toxicometabolomics (Bouhifd et al 2013 ; George et al 2010 ; Guerreiro et al 2003 ; Wetmore and Merrick 2004 ).…”

Textbook of Personalized Medicine

“…In contrast to traditional drug discovery, pharmacoproteomics integrates the mechanism of a drug's action, its side effects including toxicity, and the discovery of new drug targets in a single approach (Hess 2013 ). This approach facilitates personalized drug discovery.…”

Recent proteomic advances in developmental, regeneration, and cancer governing signaling pathways

“…The RTK RET is a key regulator in neuronal signaling activated by glia cell line‐derived neurotrophic factor family ligand and are known to be key factors in neuron survival . Pharmacoproteomics approaches have been fundamental in understanding kinase activation upon drug treatment . In one paper, Hofener et al describe an affinity‐based pharmacoproteomics approach that enables kinase activity profiling .…”