Figure 2.

Linkerology and ternary complex formation. The linker length plays an important role in PROTAC-induced degradation. (i) Short linkers that do not allow each target protein to engage its respective ligand will not allow ternary complex formation and thus will fail to induce degradation. (ii) The ideal linker length(s) will allow for strong and stable ternary complexes to form with positive cooperativity. (iii) As linker length increases, due to increased flexibility, the number of possible ternary complex conformers increases. This increased flexibility is tolerated differently by each E3:POI pair. Thus, the“ideal linker” will vary for each neosubstate and E3 pair.