Novel strategies and promising opportunities for targeted protein degradation: An innovative therapeutic approach to overcome cancer resistance

Targeted Protein Degradation is an emerging and rapidly developing technique for designing and treating new drugs. With the emergence of a promising class of pharmaceutical molecules, Heterobifunctional Proteolysis -targeting chimeras (PROTACs), TPD has become a powerful tool to completely tackle pathogenic proteins with traditional small molecule inhibitors. However, the conventional PROTACs have gradually exposed potential disadvantages of poor oral bioavailability and pharmacokinetic (PK) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics due to their larger molecular weight and more complex structure than the conventional small-molecule inhibitors. Therefore, 20 years after the concept of PROTAC was proposed, more and more scientists are committed to developing new TPD technology to overcome its defects. And several new technologies and means have been explored based on PROTAC to target undruggable proteins. Here, we aim to comprehensively summarize and profoundly analyze the research progress of targeted protein degrada-tion based on PROTAC targeting the degradation of undruggable targets. In order to clarify the significance of emerging and highly effective strategies based PROTACs in the treatment of various diseases especially in over-coming drug resistance in cancer, we will focus on the molecular structure, action mechanism, design concepts, development advantages and challenges of these emerging methods(e.g., aptamer-PROTAC conjugates, antibody-PROTACs and folate-PROTACs).(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Targeted Protein Degradation (TPD) is a powerful technique for designing and treating new drugs, particularly in overcoming drug resistance in cancer. However, traditional PROTACs have shown potential disadvantages, such as poor oral bioavailability and pharmacokinetics. Scientists are now focused on developing new TPD technologies to overcome these drawbacks.