Figure 6.

Effect of PROTAC linker length and conjugation site. A. In a representative PROTAC synthesis by Cyrus et al. [65], 20 was reacted with DSG to install an amide-linked alkyl linker. The product 21 was then reacted with the E3-binding pentapeptide sequence to displace the second succinimidyl moiety and obtain PROTAC 22; B. commercially available linker building blocks used by Cyrus et al. [65], include DSG (23), DSS (24), and Fmoc-protected acid 25. The structure of oestradiol (26) is shown with arrows pointing to potential sites of linker conjugation; C. extension of the PEG linker in EGFR and HER2 degrader 27 by one unit abolished HER2 activity to afford selective EGFR PROTAC 28