Targeting the Architecture of Deregulated Protein Complexes in Cancer

Abstract

The architectures of central signaling hubs are precisely organized by static and dynamic protein-protein interactions (PPIs). Upon deregulation, these PPI platforms are capable to propagate or initiate pathophysiological signaling events. This causes the acquisition of molecular features contributing to the etiology or progression of many diseases, including cancer, where deregulated molecular interactions of signaling proteins have been best studied. The reasons for PPI-dependent reprogramming of cancer-initiating cells are manifold; in many cases, mutations perturb PPIs, enzyme activities, protein abundance, or protein localization. Consequently, the pharmaceutical targeting of PPIs promises to be of remarkable therapeutic value. For this review we have selected three key players of oncogenic signaling which are differently affected by PPI deregulation: two (the small G proteins of the RAS family and the transcription factor MYC) are considered "undruggable" using classical drug discovery approaches and in the case of the third protein discussed here, PKA, standard kinase inhibitors, may be unsuitable in the clinic. These circumstances require alternative strategies, which may lie in pharmaceutical drug interference of critical PPIs accountable for oncogenic signaling.

Keywords: AKAP; Binary interaction; MYC; PKA; Protein kinases; Protein–protein interactions; RAF; Small molecule inhibition; Transcription factors.