Targeting cell signaling pathways for drug discovery: an old lock needs a new key.
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.
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. aggarwal@mdanderson.org
Bharat B
BB
Aggarwal
Gautam
G
Sethi
Veera
V
Baladandayuthapani
Sunil
S
Krishnan
Shishir
S
Shishodia
D000818:Animals; D018951:Antigens, CD20 / Q000096:biosynthesis; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D006973:Hypertension / Q000628:therapy; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D061988:Proteasome Inhibitors; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018951:Antigens, CD20; D016861:Cyclooxygenase Inhibitors; D061988:Proteasome Inhibitors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors