PROTAC Synthesis  (PROTAC合成)

PROTAC molecules are generally composed of three parts: ligand for target protein, linker and ligand for E3 ligase. “Click chemistry” reactions provide an accessible and tunable strategy for the selection of synthetic linkers and lay a solid foundation for the development of a diverse library of PROTACs in biomedical research. The copper-catalyzed reaction is typically high yielding, requiring stoichiometric quantities of each component and boasts excellent functional group compatibility under mild reaction conditions. This approach would allow for the parallel synthesis of libraries of PROTACs provided the necessary azides and alkynes could be prepared. For example, click chemistry was utilized to prepare a library of PROTACs based on entinostat a class I histone deacetylase (HDAC) inhibitor in clinical trials. Recently, an advanced PROTAC technology was developed, namely CLIPTAC (in-cell click-formed proteolysis-targeting chimeras), with two precursor components combined by bioorthogonal “click” reaction.