Not the comfy chair! Cancer drugs that act against multiple active sites

Abstract

ABSTRACTIntroduction: Discoveries of novel signal transduction pathways in the 1990s stimulated drug companies to develop small molecule tyrosine kinase and serine / threonine kinase inhibitors which were based on catalytic site inhibition. All kinases bind ATP and catalyze phosphate transfer and, therefore, inhibitors that block ATP binding and its metabolism would be predicted to have a known on-target specificity but were also likely to have many unknown or unrecognized targets due to similarities in all ATP binding pockets. This on-target off-target biology of kinase inhibitors, which exhibit a “signal” in the clinic, means that therapeutically valuable agents are acting through unknown biological processes to mediate their anti-tumor effects.Areas covered: This perspective discusses drug therapies whose actions cannot be explained by their actions on the original targeted kinase; it concludes with a methodology to screen for changes in cell signaling via in-cell western immunoblotting.Expert opinion: Most malignancies do not depend on survival signaling from one specific mutated proto-oncogene, especially for previously treated malignancies where multiple clonal variants of the primary tumor have evolved. Hence, the concept of a highly “personalized medicine” approach fails because it is unlikely that a specific therapy will kill all clonal variants of the tumor.