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).
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.
