Anticancer Therapy with Proteolysis-targeting Chimeras PROTACs Targeting Towards the Tumor-microenvironment: Development, Current State and Prospects

Targeted protein degradation is a rapidly expanding area that offers hope for novel approaches to combat drug resistance. The creation of heterobifunctional proteolysis-targeting chimeras PROTACs, a new group of pharmaceutical compounds, has made TPD a useful method for completely getting rid of harmful proteins using regular small-molecule inhibitors. A big plus is that PROTACs can target multi-domain proteins that cannot be broken down. This is the case, particularly for proteins lacking a conserved interaction surface for small-molecule ligands SMIs and featuring smooth surfaces. Poor oral bioavailability and pharmacokinetic PK and ADMET absorption, distribution, metabolism, excretion, and toxicity characteristics are among the long-term issues with traditional PROTACs. Their larger size and more complex structure set them apart from other smallmolecule inhibitors, which is why they are so effective. Clinical studies have been conducted on a plethora of PROTAC compounds in the past 20 years, all with the goal of inducing the degradation of targets relevant to cancer. In this article, we closely examine the major developments and recent advancements in PROTAC technology. We seek to summarize and fully assess PROTAC-based targeted protein degradation studies on "undruggable" targets. Discussing their molecular structure, action mechanism, design concepts, development benefits, and obstacles will help to illustrate the significance of developing highly successful PROTAC-based techniques in treating many illnesses, including cancer treatment resistance.