The degradation ability of most E3 ligases has not been fully exploited. On the other hand, studies show that the linker segment is also critical for PROTAC design. It has been shown that the linker segment is closely associated with the pharmacokinetic properties and protein degradation ability of PROTACs . Especially, it plays a pivotal role in maintaining the conformational stability of PROTAC ternary structure (PTS) (ie. the POI-PROTAC-E3 complex), since an appropriate linker fragment can ensure the energetically stable binding conformation of E3 ligand and warhead of POI , thus forming a stable ternary complex. However, available experience for linker design is still limited. Most of earlier linker fragments come from derived PEG chain due to its high flexibility and ease of synthesis. On this basis, various flexible linker fragments have been developed for PROTAC. Recently, relatively rigid linker fragments have also been proposed exemplified by the AR (androgen receptor) targeted PROTAC compounds in the clinical stage . Thus, developing methodology for PROTAC linker design is urgently needed for PROTAC discovery.