Sakanyan, V.; Iradyan, N.; Alves de Sousa, R. Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer. BioTech2023, 12, 57.
Sakanyan, V.; Iradyan, N.; Alves de Sousa, R. Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer. BioTech 2023, 12, 57.
Sakanyan, V.; Iradyan, N.; Alves de Sousa, R. Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer. BioTech2023, 12, 57.
Sakanyan, V.; Iradyan, N.; Alves de Sousa, R. Targeted Strategies for Degradation of Key Transmembrane Proteins in Cancer. BioTech 2023, 12, 57.
Abstract
Targeted protein degradation is an attractive technology for cancer treatment due to its ability to overcome the unpredictability of 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 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 have developed 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 targeted degradation of the transmembrane receptor, simultaneously activating both systems of protein degradation in cells. Damage to EGFR signaling pathways promotes inactivation of Bim sensor protein phosphorylation, which leads to disintegration of the cytoskeleton, followed by 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 that the fewer cancer cells survive, the fewer chemotherapy-resistant mutants appear.
Keywords
cancer chemotherapy; transmembrane receptors; EGFR; targeted protein degradation; furfuryl-quinolin-triazole-thiol chemicals
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
