Biology Reference
In-Depth Information
potencies, many have off-target effects, and moreover, in
vitro potency does not correlate with therapeutic dose
[102]
. These findings, corroborated by our own, counteract
the assumption of the MDD strategy that compounds with
high in vitro potency will translate into low-dose thera-
peutics in vivo. There is no reason to believe that chemical
probes would behave any differently; therefore, it follows
that probes that meet these criteria are not likely to be
superior as molecular tools for the elucidation of gene
function.
The failures of the in vitro MDD paradigm naturally
prompted a closer look at drugs that were successfully
developed before this paradigm was adopted, using systems
biology tools to gain a detailed yet comprehensive picture
of the cellular response to each drug. Our chemogenomic
data are consistent with other studies in demonstrating
that most successful drugs exhibit polypharmacology.
Meanwhile,
scale have given us a greater appreciation of the complexity
of the cell, revealing many dependencies within as well as
between functional modules. With this in mind, the poly-
pharmacology of many drugs is now considered critical to
therapeutic efficacy.
Chemogenomic profiling holds much promise towards
an increased understanding of the mechanisms of drug
action and the cellular response to chemical stress from the
in vivo perspective of the cell. Combined with other
systems-level approaches, these efforts are creating the
foundation for a deeper understanding of disease, and
ultimately, for a more effective polypharmacology-based
drug discovery paradigm.
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NCI
National Cancer Institute (USA)
NIH
National Institute of Health (USA)
NME
New Molecular Entity
PDR
Pleiotropic Drug Resistance
SGA
Synthetic Genetic Array
UPR
Unfolded Protein Response
YDP
Yeast Deletion Project
YGP
Yeast Genome Project
YKO
Yeast KnockOut
