Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer

Abstract

Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of the small molecule inhibitors that cause resistance mutations. In recent years, various targeted protein degradation strategies have been developed based on the ubiquitin–proteasome system in the cytoplasm or the autophagy–lysosomal system during endocytosis. In this review, we describe and compare technologies for the targeted inhibition and targeted degradation of the epidermal growth factor receptor (EGFR), one of the major proteins responsible for the onset and progression of many types of cancer. In addition, we develop an alternative strategy, called alloAUTO, based on the binding of new heterocyclic compounds to an allosteric site located in close proximity to the EGFR catalytic site. These compounds cause the targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to the EGFR signaling pathways promotes the inactivation of Bim sensor protein phosphorylation, which leads to the disintegration of the cytoskeleton, followed by the detachment of cancer cells from the extracellular matrix, and, ultimately, to cancer cell death. This hallmark of targeted cancer cell death suggests an advantage over other targeted protein degradation strategies, namely, the fewer cancer cells that survive mean fewer chemotherapy-resistant mutants appear.