review · Bioconjugate Chemistry
Targeted protein degradation uses small molecules to selectively eliminate disease-causing proteins. The process operates through biological pathways such as proteasome-mediated, lysosome-mediated, and autophagy-mediated degradation. Having demonstrated strong promise in preclinical investigations, this therapeutic approach is currently being translated to address conditions including cancer, infectious diseases, and neurodegenerative disorders. A major focus of recent work is the use of proteolysis targeting chimeras, known as PROTACs, as a chemical modality for immunotherapy. Current assessments track the progress of translating these molecular tools from scientific discoveries into practical technological achievements, alongside evaluating the major obstacles and future prospects for targeted protein degradation in immunotherapeutic applications.
Traditional drugs often only inhibit disease proteins temporarily, but targeted protein degradation provides a way to completely remove problematic proteins from cells. Expanding this capability into immunotherapy could lead to new treatments for conditions that are currently hard to manage, including severe cancers and neurodegenerative disorders.
The primary application lies in developing small-molecule immunotherapies for pharmaceutical developers targeting cancer, neurodegenerative disorders, and infectious diseases. While the field has demonstrated preclinical promise and is actively working on translation, the technology remains in development as researchers navigate significant obstacles prior to widespread clinical and market adoption.
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Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins that cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated degradation, and autophagy-mediated degradation. This approach has shown great promise in preclinical studies and is now being translated to treat numerous diseases, including neurodegenerative diseases, infectious diseases, and cancer. This review discusses the latest advances in TPD and its potential as a new chemical modality for immunotherapy, with a special focus on the innovative applications and cutting-edge research of PROTACs (Proteolysis TArgeting Chimeras) and their efficient translation from scientific discovery to technological achievements. Our review also addresses the significant obstacles and potential prospects in this domain, while also offering insights into the future of TPD for immunotherapeutic applications.
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DOI: 10.1021/acs.bioconjchem.4c00253
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