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Breakthrough Drug Discovery: What is PROTAC and why can it break the "undruggable" barrier?
With the rapid progress of biomedicine, many disease proteins that were previously considered untargetable are now gradually becoming new focuses of research. Among them, PROteolysis-TArgeting Chimeras (PROTACs), as a new technology, is changing the scope of drug development. PROTAC technology, developed by Professor Craig M. Crews of Yale University, has ushered in a new era of targeted protein degradation by magically combining specific proteins with the degradation machinery of cells, attracting extensive research and investment.
Principle of PROTAC
PROTAC is a bifunctional molecule that can simultaneously bind to the target protein and E3 ubiquitin ligase, thereby catalyzing the ubiquitination of the target protein. This process marks the target protein for recognition and degradation by the cell's proteasome. Crews and his team first proposed this concept in 2001, and the development of their technology has made many proteins that were originally considered "undruggable" now become targets for therapeutic drugs.
"The emergence of PROTAC technology provides a new approach to drug development, allowing researchers to target proteins with inaccessible active sites, especially in the field of cancer treatment."
The benefit of this new approach is that it can not only selectively degrade disease-related proteins, but also reduce damage to normal cells, so it is widely regarded as a potential therapeutic miracle. Especially for cancer treatment, PROTAC makes it possible to target proteins with drug resistance characteristics, thus overturning researchers' previous cognition.
Research History and Development
Professor Craig M. Crews' research history can be traced back to his graduate student days at Harvard University. In his early research, he successfully isolated and cloned MEK1, an important signal transduction molecule, laying the foundation for the subsequent development of anti-cancer drugs targeting it. Meanwhile, Crews further developed potent proteasome inhibitors such as Epoxomicin during his research, and subsequent RO ketone compounds became important precursors for the multiple myeloma drug carfilzomib.
"Our deep understanding of the pathology supports the development of these innovative treatments, which in turn attracts a lot of attention and funding."
The success of PROTAC not only relies on Professor Crews' basic research, but also benefits from his collaboration with multiple biotechnology companies. Crews has founded several companies, such as Arvinas, that aim to use PROTAC technology to develop therapeutics for cancer and neurodegenerative diseases.
Clinical Prospects and Challenges
In the latest clinical trial, Arvinas' PROTAC drug ARV-471 has been confirmed to target estrogen receptors and has now entered Phase 3 trials, focusing on the treatment of metastatic breast cancer. The drug has gained widespread attention due to its good oral absorption, which addresses a major challenge in PROTAC drug development.
"The broad application prospects of PROTACs are encouraging the scientific community and the biopharmaceutical industry to actively invest resources to promote the development of this technology."
However, the success of PROTAC technology in clinical applications still requires solving many challenges, including drug biocompatibility and specificity, drug synthesis process and other issues. In addition, as relevant research deepens, the academic community's discussion on the potential application scenarios of this technology has become increasingly eye-catching.
Conclusion
PROTAC technology is a revolution in drug development, opening up new possibilities for fighting future diseases. As this technology develops further, the scientific community expects to be able to use it to overcome more difficult problems that were previously unattainable. Looking to the future, will PROTAC become the mainstream method of drug development?
