Construction of PROTAC Library via Liquid-Phase Synthesis Enabled by a Hydrophobic Tag.

Herein, we present a new synthetic strategy for PROTAC development by using hydrophobic tag-assisted liquid-phase synthesis (LPS). The hydrophobic tag enables intermediates to be purified by precipitation, thus sparing the effort of column purification. Adopting this strategy, we efficiently constructed highly diverse linker and androgen receptor (AR)-targeting PROTAC libraries. Among the 26 synthesized PROTACs, compound 25 emerged as the most potent one, exhibiting a subnanomolar DC50 value, high Dmax, and strong antiproliferative activity.