Targeted protein degradation is a therapeutic approach aimed at selectively removing specific disease-causing proteins from cells. Unlike traditional small molecule inhibitors that bind to protein active sites, targeted protein degradation involves tagging the protein of interest with a small molecule called a proteolysis-targeting chimera (PROTAC) or molecular glue. This tagging targets the protein for degradation by the cell's own proteasome machinery, leading to its breakdown into smaller peptides and amino acids.
The process typically involves three main steps:
- Recognition: The small molecule (PROTAC or molecular glue) binds to both the target protein and an E3 ubiquitin ligase enzyme.
- Ubiquitination: The E3 ligase catalyzes the attachment of ubiquitin molecules to the target protein, marking it for degradation.
- Degradation: The ubiquitinated protein is recognized by the proteasome, a cellular complex that degrades proteins into smaller peptides and amino acids, thus removing the target protein from the cell.
This approach offers several potential advantages over traditional inhibitors, such as the ability to target proteins that are considered "undruggable" by conventional methods and the potential for greater selectivity and reduced side effects. Targeted protein degradation is an active area of research and development in drug discovery for various diseases, including cancer, neurodegenerative disorders, and autoimmune diseases.
Reviews:
(1) Zhao L, Zhao J, Zhong K, Tong A, Jia D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct Target Ther. 2022 Apr 4;7(1):113. doi: 10.1038/s41392-022-00966-4. PMID: 35379777; PMCID: PMC8977435.
(2)Dong G, Ding Y, He S, Sheng C. Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery. J Med Chem. 2021 Aug 12;64(15):10606-10620. doi: 10.1021/acs.jmedchem.1c00895. Epub 2021 Jul 28. PMID: 34319094.