Recent Advances in PROteolysis TArgeting Chimeras (PROTACs)

Dear Colleagues,

PROteolysis TArgeting Chimeras (PROTACs) are innovative and exciting technologies that are rapidly gaining traction in both academic research and the pharmaceutical industry. These small molecules represent a novel approach to combating drug resistance, one of the most significant challenges in modern medicine. Unlike traditional therapies that aim to inhibit or block the activity of problematic proteins, PROTACs function by degrading the proteins themselves. This unique mechanism opens up new therapeutic possibilities, especially for previously "undruggable" proteins that cannot be effectively targeted using conventional inhibitors.

PROTACs work by linking a protein of interest (POI) to an E3 ubiquitin ligase—an enzyme that tags proteins with ubiquitin, marking them for destruction by the cell’s proteasome system. Once the protein is tagged, the cell degrades it, reducing its levels and, consequently, its disease-causing effects. This process offers a rapid and reversible method of modulating protein levels, providing distinct advantages over traditional gene-editing approaches like CRISPR, which involve permanent alterations to the genome.

The flexibility of PROTACs has demonstrated great potential not only in cancer therapy but also in addressing a broad range of diseases, including immune disorders, viral infections, and neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. Their ability to selectively target and degrade specific proteins provides a highly tailored therapeutic approach, which could overcome the limitations of small-molecule inhibitors, such as off-target effects and the eventual development of drug resistance.

However, despite their promise, there are still several challenges to overcome before PROTACs can fully transition into clinical use. These include improving their pharmacokinetics, ensuring that they can be effectively delivered to target tissues, and confirming their efficacy and safety in humans through rigorous preclinical and clinical testing. As a result, ongoing research is critical to optimize their design, improve their specificity, and enhance their delivery to the desired target cells.

In addition to PROTACs, other protein degradation technologies are emerging, including molecular glues, LYTAC (lysosome-targeting chimeras), PhotoPROTACs (light-activated PROTACs), AUTACs (autophagy-targeting chimeras), Homo-PROTACs, and RIBOTAC (ribonuclease-targeting chimera). These alternative strategies offer unique ways of targeting and degrading disease-causing proteins and further underscore the therapeutic potential of harnessing cellular degradation pathways.

For this Special Issue, we invite submissions of original research and review articles that explore the latest advancements in PROTACs. Topics of interest include the development of novel PROTACs, their roles in overcoming drug resistance, and their applications in various disease contexts. We are also particularly interested in studies focused on drug delivery systems that enhance the efficacy, bioavailability, and targeting precision of PROTACs. Submissions that provide laboratory, preclinical, or clinical evidence of PROTACs' potential in cancer therapy and other diseases are highly encouraged.

Prof. Dr. Dhimant Desai
Dr. Mourad Zerfaoui
Guest Editors

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• PROTAC
• RIBOTAC
• molecular glues
• LYTAC