Razing the scaffolding: the elimination of non-catalytic functions of kinases through targeted protein degradation

Abstract

Overexpression and activation of kinases often results in cancer initiation and progression through both catalytic and non-catalytic functions that promote rapid proliferation, growth, survival, and metastasis of cells. Catalytic functions are effectively blocked with the use of ATP-competitive inhibitors, however drug-resistant mutations are emerging all the time. Further, single-agent ATP-competitive inhibitors sometimes fail to eliminate oncogenic properties of the targeted kinase, likely due to (non-targeted) non-catalytic functions that are maintained. Non-catalytic functions – such as scaffolding roles, where the kinase may interact with other proteins to coordinate cellular activities or protect them from degradation by the proteasome – may be targeted through the development of protein–protein interaction (PPI) inhibitors, although this is a highly challenging endeavour. To overcome the limitations of classical (ATP-competitive) inhibitors (and circumvent the formidable feat required in the development of PPI inhibitors), which operate through “occupancy-driven” pharmacology, targeted protein degradation, as showcased by proteolysis targeting chimeras (PROTACs), is fast becoming a highly sought-after goal for a large plethora of protein targets, and is governed by “event-driven” pharmacology. Because PROTACs result in the degradation of the protein of interest, these compounds are predicted to both catalytic and non-catalytic functions of a targeted kinase. Herein, we focus on the development of PROTACs that target (i) the scaffolding roles of focal adhesion kinase (FAK) that are associated with the formation of signaling units involved in migration and invasion events and (ii) the scaffolding roles of Aurora-A kinase (AURKA), which play a role in the protection of MYC proteins from proteasomal degradation.