When developing new treatments, scientists aim to identify specific protein groups affected by a disease and regulate their activity to restore the body to a favorable state. Traditional drugs usually work by binding to specific regions on target proteins, disrupting their function. However, several proteins considered paramount to curing certain diseases are deemed "undruggable" due to their complex structures lacking suitable binding sites, disabling conventional drugs from targeting them. This poses a longstanding challenge in medicine, as undruggable proteins continue to elude effective therapy to this day.
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Targeted Protein Degradation (TPD) is an innovative approach in drug development that aims to selectively remove specific proteins from cells to treat diseases. Traditional drug therapies often target proteins by blocking their function with small molecules, but TPD takes on the root of the problem, getting rid of the disease-associated proteins entirely.
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At the core of TPD are molecules called Proteolysis Targeting Chimeras (PROTACs). PROTACs are designed to recruit a protein of interest (POI) and an E3 ubiquitin ligase simultaneously. The E3 ligase is an enzyme responsible for adding a small protein called ubiquitin to the POI.
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Ubiquitin is effectively a death mark placed on the target protein that lets the proteasome (the cell’s built-in protein destruction mechanism) identify the proteins to be destroyed.
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1. PROTAC Binding: The PROTAC molecule binds to the undruggable protein and the E3 ligase simultaneously.
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2. Ubiquitination: The E3 ligase adds multiple tags called ubiquitin to the protein, creating a polyubiquitin chain for the proteasome to detect.
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3. Proteasomal Degradation: The proteasome detects the tagged protein, swiftly degrading it into harmless molecules that the cell then safely ejects.
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PROTACs offer multiple advantages over traditional small molecule inhibitors. They greatly expand the range of druggable proteins, addressing over 4,000 disease-associated proteins compared to only around 400 targeted by traditional therapies. Unlike traditional inhibitors that only block part of a protein's function, PROTACs degrade the protein entirely, eliminating all its functions. This feature may reduce drug resistance commonly observed with traditional inhibitors. Additionally, PROTACs work in a catalytic manner, allowing them to be effective at low concentrations, potentially reducing toxic side effects. Further research into PROTACs has also revealed phosphoPROTAC and photoPROTAC variants, which can trigger TPD using activated kinase signaling and light-dependent reactions respectively.
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Other TPD technologies are also under development, including SNIPERs (Specific and Non-genetic IAP-dependent Protein Erasers) which take out both the target proteins and those responsible for inhibiting cell death, and Hydrophobic Tagging, which destroys the structural integrity of target proteins without using ubiquitination.
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Several major players are investing in Targeted Protein Degradation (TPD) technologies. Plexium, a biotech company, raised $102 million in funding and has a cell-based screening platform called DELPhe. Monte Rosa Therapeutics secured $95 million in a Series C funding round and focuses on TPD. Lycia Therapeutics raised $105 million in their Series B funding and targets extracellular and membrane-bound proteins. Cedilla Therapeutics, backed by Third Rock Ventures, concentrates on harnessing protein degradation pathways and raised around $83 million. These companies are at the forefront of TPD innovation, attracting significant investments from venture capital firms and pharmaceutical companies due to the potential of TPD in revolutionizing drug development.
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While TPD shows great promise, it remains in its infancy stage, and more research is needed to fully understand its potential, optimize PROTAC designs, and ensure safety and efficacy in clinical applications. As more studies are conducted and data is gathered, TPD has the potential to revolutionize medicine and open up new treatment possibilities for previously challenging disease states.

To learn more about the technology you can check out the official website.