Proteolysis-Targeting Chimeras (PROTACs) are emerging as a promising tool in cancer therapy, representing a novel approach to targeted protein degradation. Unlike traditional small-molecule inhibitors that block the activity of proteins, PROTACs are designed to degrade specific proteins within cells, effectively eliminating them. This innovative mechanism has attracted significant interest in cancer research, as many cancers are driven by the overexpression or mutation of proteins that promote uncontrolled cell growth. PROTACs offer a potential solution for targeting proteins that were previously considered “undruggable,” expanding the possibilities for cancer treatment. Currently, there are more than 25 PROTAC drugs in clinical trials for treatment of cancer according to Neeraj Chawla, Research Head, Kuick Research. He further added that first drug is expected to be commercially available in market by 2027.
Download Report: https://www.kuickresearch.com/ccformF.php?t=1728551968
PROTACs consist of two functional components: one that binds to the protein of interest (POI) and another that binds to an E3 ubiquitin ligase. These two are connected by a linker. The design of PROTACs enables the recruitment of the ubiquitin ligase to the POI, tagging the protein for degradation by the proteasome, the cellular machinery responsible for breaking down proteins. This results in the destruction of the disease-causing protein, effectively removing it from the cell. By taking advantage of the cell’s natural degradation pathways, PROTACs can selectively and efficiently eliminate proteins that play a crucial role in cancer development and progression.
One of the key advantages of PROTACs over conventional therapies is their ability to degrade the entire protein, rather than merely inhibiting its activity. In many cases, inhibition is not sufficient to halt the progression of cancer, as the protein may continue to exert its effects even in a partially inhibited state. Additionally, proteins often develop resistance to inhibitors over time, diminishing the long-term efficacy of traditional therapies. PROTACs address this limitation by eliminating the protein entirely, reducing the potential for resistance and leading to more sustained therapeutic effects.
PROTACs have shown promise in targeting a wide range of cancer-related proteins, including those involved in signal transduction, transcription regulation, and cell cycle control. One area of particular interest is the targeting of oncogenic kinases, which play a critical role in driving cancer cell proliferation. Kinases are often difficult to target with traditional inhibitors, as they frequently develop resistance through mutations. PROTACs offer a potential solution by degrading the kinase entirely, thereby preventing the development of resistance.
Another area where PROTACs show great potential is in the targeting of transcription factors. Transcription factors are notoriously challenging to target with small molecules, as they lack well-defined active sites for inhibitors to bind. However, PROTACs can be designed to recruit transcription factors to the ubiquitin-proteasome system, facilitating their degradation and disrupting the gene expression programs that drive cancer.
Despite their promise, there are still challenges to be addressed in the development of PROTACs for cancer therapy. One challenge is the need for precise design and optimization to ensure that PROTACs are highly selective for their target proteins. Off-target degradation could lead to unintended consequences, such as toxicity or interference with normal cellular processes. Additionally, the stability and pharmacokinetics of PROTACs must be carefully considered to ensure that they can reach their intended targets in the body and maintain their activity over time.
In conclusion, PROTACs represent an exciting and innovative approach to cancer therapy, offering the potential to target previously “undruggable” proteins and overcome the limitations of traditional inhibitors. With ongoing research and development, PROTACs have the potential to transform cancer treatment, providing new hope for patients with hard-to-treat cancers. As the field of targeted protein degradation continues to evolve, PROTACs are likely to play an increasingly important role in the future of oncology.
