Can Proteins be Modified to Fight Diseases and Cancer?

Alternative Title: Medical Writer Michael A. S. Guth’s Summary of External Research on Cancer Treatment Using Proteolysis Targeting Chimera (PROTAC) Biochemistry and the Body’s Ubiquitin-Proteasome System (UPS) Natural Degradation Process to Eliminate Disease-Causing Proteins. Oral PROTACs have shown encouraging clinical trial results in the treatment of some genotypes (ER+/HER-) of breast cancer and in previously treated metastatic castration-resistant prostate cancer (mCRPC). PROTACs degrade a targeted protein by attaching ubiquitin molecules (a process called “ubiquitinating”) the target proteins and stopping tumor growth. PROTACs—which are bivalent chemical protein degraders—are multifunctional molecules that act on specific endogenous proteins through the E3 ubiquitin ligase pathway.

Protein degradation is required for maintaining homeostasis of cell proteins and to regulate numerous cell processes, such as gene transcription, DNA pairing, cell cycle control, and apoptosis. The UPS is a crucial way to specifically degrade proteins that are involved in various metabolic activities, mainly including cyclin, spindle related proteins, cell surface receptors (epidermal growth factor receptor, etc.), transcription factors (NF-κB, etc.), tumor suppressor factors such as p53, oncogene products, and intracellular denaturing proteins, whose deregulation is related to the pathogenesis of many diseases. UPS relies on adenosine triphosphate (ATP) and consists of two steps: polyubiquitination of target protein and proteolysis of polyubiquitin by 26S proteolytic enzyme complex. 

Compared to UPS, two conventional treatment methods, small molecule inhibitors (SMIs) and monoclonal antibodies (mAbs), suffer from some inherent limitations due to their mechanisms of actions. The FDA has approved over 62 SMIs that target about 20 different protein kinases. However, for most protein kinases, there is a lack of suitable active sites to target. In addition, molecule-targeted therapy is easy to induce drug resistance. mAbs have a large molecular weight and mainly target proteins located at the plasma membrane.

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