Targeted protein degradation harnesses the cell’s own machinery to eliminate disease-causing proteins, offering a promising new avenue for drug development.
Understanding Targeted Protein Degradation
Traditional drug discovery focuses on directly controlling the activity of proteins, which play essential roles in our bodies. Scientists develop drugs that can either enhance or inhibit the activity of specific proteins to treat diseases. However, there are limitations to this approach, especially when it comes to targeting proteins that are difficult to regulate.
Recently, a new and exciting approach called targeted protein degradation has made a breakthrough in drug development. The approach takes advantage of the natural machinery in our cells that helps break down and remove proteins.
Our cells contain a mechanism known as the ubiquitin-proteasome system, which plays a vital role in identifying and dismantling damaged or no proteins that are no longer required.
Targeted protein degradation utilizes this system by employing specific molecules called degraders or degronics. These molecules work by redirecting the ubiquitin-proteasome system's attention towards disease-causing proteins, marking them for degradation and subsequent removal from the cell.
Mechanisms of Targeted Protein Degradation
One of the key technologies in targeted protein degradation is called PROteolysis Targeting Chimeras (PROTAC). It works by using a small molecule that can bind to a disease-associated protein and recruit the cell’s own machinery to destroy and remove that protein.
In addition to PROTAC, there are other strategies being developed, such as molecular glue, Lysosome-Targeting Chimaera (LYTAC), and Antibody-based PROTAC (AbTAC). These different technologies expand the possibilities of targeted protein degradation and provide new insights into drug discovery.
Applications of Targeted Protein Degradation
Targeted Protein Degradation shows promise in treating many conditions, including cancer, neurodegenerative diseases, inflammatory diseases and viral infections.
Several targeted protein degradation (TPD) molecules, primarily utilizing PROTAC technology, have demonstrated promising therapeutic effects in clinical trials and studies focused on cancer treatment.
The estrogen receptor (ER) plays a crucial role in breast cancer development by controlling gene expression. ARV-471, a PROTAC molecule created by Arvinas, specifically targets ER.
In laboratory tests using animal models, ARV-471 efficiently degrades ER and significantly reduces tumor size. Currently, ARV-471 is undergoing phase II clinical trials, where it can be administered alone or in combination with a CDK4/6 inhibitor. In clinical experiments, ARV-471 has shown positive characteristics, such as being orally available and well-tolerated by patients.
In 2016, researchers from the Chen and Li groups made a significant breakthrough by using a PROTAC molecule to target tau protein, which is associated with neurodegenerative diseases (NDs). This was the first attempt to apply PROTAC technology for ND treatment.
The molecule they designed combines different parts, including a tau-binding peptide, a linker, a VHL-binding peptide, and a cell-penetrating peptide. When this molecule is introduced, it leads to significant degradation of tau protein and reduces the harmful effects of Aβ, which is involved in neurotoxicity.
Targeted Protein Degradation Clinical Trials
Several PROTACs have advanced to clinical trials, offering hope for new therapies in the near future. For instance, Arvinas is developing ARV-110, a degrader targeting the androgen receptor, for prostate cancer (in phase II). They are also working on ARV-471, a degrader for the estrogen receptor, for breast cancer (in phase II).
Bristol-Myers Squibb, Kymera Therapeutics, and Dialectic Therapeutics are also conducting phase I trials for degraders targeting the androgen receptor, IRAK4 for autoimmune disorders, and BCL-xL for various cancers, respectively.
These clinical trials bring optimism that patients may soon have access to new and improved treatments. The early signs of tolerability and efficacy observed in these trials also reassure the dedicated scientists worldwide who are striving to develop PROTACs for treating various diseases with unmet medical needs.
In summary, PROTACs are already revolutionizing protein studies and disease treatments. The future of targeted protein degradation looks promising, with continued advancements in research and development.
Challenges in Targeted Protein Degradation
The PROTAC technology still faces several challenges. One major challenge is related to the properties of the molecules themselves. PROTAC molecules can be quite large, which makes it difficult for them to enter cells or be taken orally, affecting their effectiveness. On the other hand, molecular glues, which are smaller, have some advantages but are more challenging to design in a precise manner.
Another challenge is the limited availability of E3 ubiquitin ligases. The human genome contains more than 600 of these ligases, but only a few, such as VHL, CRBN, IAPs, and MDM2, have been successfully utilized to degrade specific target proteins. This limitation restricts the range of proteins that can be targeted for degradation.
Additionally, there is a concern regarding toxicity. PROTAC molecules can potentially cause more toxicity compared to small molecule inhibitors. This is because PROTACs lead to the degradation of entire target proteins rather than simply inhibiting them. It is essential to carefully assess and minimize the potentially toxic effects of PROTAC molecules during the drug development process.
Addressing these challenges requires ongoing research and development efforts to optimize the design and properties of PROTAC molecules, expand the repertoire of E3 ubiquitin ligases, and ensure the safety of these compounds for therapeutic applications.
Compared to PROTAC and molecular glue, developing lysosome-based targeted protein degradation (TPD) technologies is still in its early stages. There is much we still need to understand about how each of these technologies works.
To advance lysosome-based TPD, scientists need to expand the range of receptors that can be targeted specifically to lysosomes. Currently, only a couple of receptors, namely CI-MPR and ASGPR, are being used for lysosome targeting in LYTAC and similar technologies.
They also need to study and understand the AUTAC, ATTEC, and AUTOTAC molecules in more detail, including their structure-activity relationship and how they work. This will help develop these autophagy-based technologies as a general method for protein degradation, similar to PROTAC.
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Li, H., Dong, J., Cai, M., Xu, Z., Cheng, X.-D. and Qin, J.-J. (2021). Protein degradation technology: a strategic paradigm shift in drug discovery. Journal of Hematology & Oncology, 14(1). doi.org/10.1186/s13045-021-01146-7.
Zhao, L., Zhao, J., Zhong, K., Tong, A. and Jia, D. (2022). Targeted protein degradation: mechanisms, strategies and application. Signal Transduction and Targeted Therapy, 7(1). doi.org/10.1038/s41392-022-00966-4.