Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy 1

Over the past decade, inhibition of the kinase activities of oncogenic proteins using small molecules and antibodies has been a mainstay of our anticancer drug development effort, resulting in several Food and Drug Administration–approved cancer therapies. The clinical effectiveness of kinase-targeted agents has been inconsistent, mostly because of the development of resistance. The expression and function of oncoproteins and tumor suppressors are regulated by numerous posttranslational protein modifications including phosphorylation, ubiquitination, and acetylation; hence, targeting specific posttranslational protein modifications provides for an attractive strategy for anticancer drug development. The present review discusses the hypothesis that targeted degradation of an oncoprotein may overcome many of the shortcomings seen with kinase inhibitors and that the approach would enable targeted inhibition of oncogenic proteins previously thought to be undruggable.