TY - JOUR
T1 - Targeting cell signaling pathways for drug discovery
T2 - An old lock needs a new key
AU - Aggarwal, Bharat B.
AU - Sethi, Gautam
AU - Baladandayuthapani, Veera
AU - Krishnan, Sunil
AU - Shishodia, Shishir
PY - 2007/10/15
Y1 - 2007/10/15
N2 - In this age of targeted therapy, the failure of most current drug-discovery efforts to yield safe, effective, and inexpensive drugs has generated widespread concern. Successful drug development has been stymied by a general focus on target selection rather than clinical safety and efficacy. The very process of validating the targets themselves is inefficient and in many cases leads to drugs having poor efficacy and undesirable side effects. Indeed, some rationally designed drugs (e.g., inhibitors of receptor tyrosine kinases, tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), bcr-abl, and proteasomes) are ineffective against cancers and other inflammatory conditions and produce serious side effects. Since any given cancer carries mutations in an estimated 300 genes, this raises an important question about how effective these targeted therapies can ever be against cancer. Thus, it has become necessary to rethink drug development strategies. This review analyzes the shortcomings of rationally designed target-specific drugs against cancer cell signaling pathways and evaluates the available options for future drug development.
AB - In this age of targeted therapy, the failure of most current drug-discovery efforts to yield safe, effective, and inexpensive drugs has generated widespread concern. Successful drug development has been stymied by a general focus on target selection rather than clinical safety and efficacy. The very process of validating the targets themselves is inefficient and in many cases leads to drugs having poor efficacy and undesirable side effects. Indeed, some rationally designed drugs (e.g., inhibitors of receptor tyrosine kinases, tumor necrosis factor (TNF), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), bcr-abl, and proteasomes) are ineffective against cancers and other inflammatory conditions and produce serious side effects. Since any given cancer carries mutations in an estimated 300 genes, this raises an important question about how effective these targeted therapies can ever be against cancer. Thus, it has become necessary to rethink drug development strategies. This review analyzes the shortcomings of rationally designed target-specific drugs against cancer cell signaling pathways and evaluates the available options for future drug development.
KW - Cancer
KW - Cell signaling
KW - Drug-discovery
KW - Natural products
KW - Targeted therapy
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U2 - 10.1002/jcb.21500
DO - 10.1002/jcb.21500
M3 - Review article
C2 - 17668425
AN - SCOPUS:35048841732
SN - 0730-2312
VL - 102
SP - 580
EP - 592
JO - Journal of cellular biochemistry
JF - Journal of cellular biochemistry
IS - 3
ER -