165the future. Even the most useful disease biomarkers such as prostate-specifi c
antigen, are proteins. The pathomechanism-based medicine of the future will require
input from proteomics for the understanding of how protein pathways link genes to
diseases. It is important to understand how the protein function gets deranged in
order to design molecules that will correct the aberrant protein.
After a lead molecule is identifi ed, one needs to confi rm the effi cacy of the drug
through the expected mechanism. Proteomics can be used to study the mode of
action of drugs by comparing the proteome of the cells in which the drug target has
been eliminated by molecular knockout techniques or with small molecule inhibi-
tors believed to act specifi cally on the same target.
Proteomic techniques enable study of protein expression levels, modifi cations,
location and function in high throughput automated systems. Because proteome
analysis can produce comprehensive molecular description of the differences
between normal and diseased states, it can be used to compare the effect of candi-
date drugs on the disease process. Proteomics can be integrated into the drug discov-
ery process along with the genomic and chemical drug discovery. Proteomics may
emerge as a powerful approach for directly identifying highly predictive pharma-
cogenomic biomarkers in blood or other body tissues. Defi nition and validation of
drug targets by proteomics will have the following advantages for drug discovery:
- Fewer dropout compounds in the developmental pipeline
- Rational drug design of compounds with fewer side effects
Role of Proteomics in Clinical Drug Safety
Clinical chemistry endpoints for routine animal toxicity testing and clinical trial
safety monitoring have been used for over 25 years. Drug-induced damage to the
liver is the most common type of toxicity that results in a treatment being withdrawn
from clinical trials or from further marketing. Similarly, cardiotoxicity is a frequent
occurrence in patients undergoing cancer chemotherapy. However, the currently
available biomarkers for these common types of drug-induced toxicities have lim-
ited sensitivity or predictive value. The proteomic tools available today are enabling
us to tap into the wealth of genome sequence information to discover and carefully
investigate associations of thousands of proteins with drug-induced toxicities that
are now not easily monitored.
Toxicoproteomics
Proteomics can increase the speed and sensitivity of toxicological screening by
identifying protein markers of toxicity. Proteomics studies have already provided
insights into the mechanisms of action of a wide range of substances, from metals
Role of Proteomics in Clinical Drug Safety