Versatile One-Pot Synthesis of Hydrophobic Tags by Multicomponent Reactions

Among the various strategies being developed in the field of protein degraders, HyTags remain relatively underexplored, despite their advantages over PROTACs. Their synthesis typically involves multistep procedures, including the use of coupling reagents and protection/deprotection steps. To develop a more sustainable and streamlined approach, we designed a versatile multicomponent platform that generates HyTags with diverse linkers and hydrophobic moieties in high yields. Using (+)-JQ1 as the POI ligand, we synthesized a series of BRD4-targeting HyTags and discovered that compound 23 induces degradation of BRD4 via the autophagy-lysosome pathway through ER stress. This finding further supports the valuable application of this synthetic methodology in the search for effective degraders.