Biology Reference
In-Depth Information
Chapter 8
Chemogenomic Profiling: Understanding
the Cellular Response to Drug
Anna Y. Lee
1
, Gary D. Bader
1
,
2
, Corey Nislow
1
,
2
,
3
and Guri Giaever
1
,
2
,
4
1
The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada,
2
Department of Molecular
Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada,
3
Banting and Best Department of Medical Research, University of Toronto,
4
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada
Toronto, Ontario M5S 3E1, Canada,
Chapter Outline
Impact of the Human Genome Project on Healthcare
and Biology
Target Identification/Mechanism of Drug Action
160
153
Compendium RNA Expression Approaches to Predict
the Drug Target/Mechanism of Drug Action
Healthcare: Few New Therapies
153
161
Biology: The Cell is More Than the Sum of its Parts
154
Fitness-based Chemogenomic Profiling Approaches
to Identify the Drug Target/Mechanism of Drug Action 162
HIPHOP
Impact of Genomics: Shifting the Perceptions of Drug and
Cellular Behavior
154
162
The Cell is a Highly Interactive Robust System
154
Chemical
e
Genetic Interactions Reveal Conditional
Yeast: A Pioneer and Driver of All Things 'Omic'
155
Essentiality
163
The Yeast Genome Project
155
Identification of Novel Chemical Probes
163
The Yeast Deletion Project
155
HIP Predicts the Yeast Druggable Genome is Double that of
Current Estimates
Impact of Yeast in the Development of Genomic
Technologies
164
157
Co-Inhibition Reflects Structure and Therapeutic Class
164
Drug Behavior is Promiscuous
158
Co-Fitness Predicts Gene Function
166
Modern Drug Discovery: A Historical Perspective
158
The Multi-Drug Resistance Network
166
Drugs are Promiscuous; the Discovery
of Polypharmacology
Global View of the Mechanisms Involved in Cellular
Resistance to Small Molecules
159
166
Phenotypic Screening
159
Chemical Structures Associated with MDR Biological
Processes
Chemical Probes; Like Drugs, but Designed to Serve as
Tools to Study Gene Function
170
159
Conclusions and Future Challenges
171
Chemogenomics
160
References
172
IMPACT OF THE HUMAN GENOME
PROJECT ON HEALTHCARE
AND BIOLOGY
Healthcare: Few New Therapies
A decade after the completion of the human genome project
(HGP), the much anticipated improvements in healthcare
and the promised delivery of new therapies have yet to be
realized. As the primary source of new therapies, the
pharmaceutical industry has been in a position to exploit
the hundreds of potential new targets revealed by the HGP.
The HGP and the genetic variation studies that followed,
however, revealed that most diseases are more complex
than had been anticipated. As a result, drug discovery
remains as challenging as ever. For example, despite
enormous increases in research and development spending,
the number of novel small-molecule drugs emerging from
the pharmaceutical industry each year continues to decline.
Combined with the crippling costs required to develop
a new therapy (~1.8bn USD), most pharmaceutical execu-
tives describe the current state of drug discovery as
unsustainable. Countless analyses have searched for
underlying causes, yet none have gone beyond describing
the symptoms; for example, high attrition rates during the
