Authors
BOC Sciences
Summary
All-small molecule PROTAC achieves rapid targeted degradation and better cell permeability by using small molecular ligands to recruit target proteins and E3 ligases. It is worth noting that the heterogeneous bifunctional full-small molecule PROTAC shows better stability and biological distribution in cells, as well as passive cell entry. Various small molecules have been shown to bind to the substrate receptor proteins of several E3 ligases or CRL E3 ligase complexes, such as MDM2, cIAP1, CRBN, and VHL, for PROTAC development
Introduction
Because the degradation of the target protein can achieve the regulation of many non-enzymatic protein targets, and then greatly expand the scope of existing drug targets, the development of strategies to induce protein degradation has a long research history. Researchers who have developed protein-degrading drugs hope to use the degradation mechanism of ubiquitin proteasomes to change the fate of proteins that cause disease. To achieve this goal, they designed a small molecule with two active ends, one of which can bind to the targeted protein, while the other can bind to a protein called E3 ubiquitin ligase (E3 ubiquitin ligase)). This bifunctional small molecule forces ubiquitin to bind to targeted proteins and transport them to the cell's waste disposal station. After the proteins are degraded, they can continue to target other proteins, thus rapidly reducing the level of unwanted proteins. The design of small molecules ligand for target degradation is not irrelevant, because even small changes in ligands and crosslinkers can affect the binding to POI or E3 ligases or the formation of ternary complexes. Therefore, existing studies have slightly changed the structure of small molecules, synthesized many analogs, and screened in cells to find the best PROTAC for target degradation. The ends of these small molecules do not need to bind to the protein domain that shuts down the protein function, they only need to bind to the target for a long enough time to complete the process of ubiquitin labeling.
References
For more information, please see PROTAC Technology.
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