PROTAC Linker

PROTAC linkers can be roughly divided into two categories: flexible linkers and relatively rigid linkers. Flexible linkers are the most widely used type, mainly including alkyl linkers and polyethylene glycol (PEG) linkers. Flexible linkers, which are prevalent in PROTAC design, usually use long and flexible structures. However, this design can increase the susceptibility to oxidative metabolism in vivo. In contrast, due to the limitations of synthetic technology in the PROTAC field, relatively rigid linkers are used less frequently, including a total of 8 types. Among them, cycloalkanes, especially linkers containing piperazine and piperidine components, are often used because they increase the solubility and stability of the ternary complex. Triazole-based linkers are another commonly used rigid linker, which has high compatibility and consistent reaction rates with different functional groups due to the emergence of click chemistry reactions, using copper-catalyzed 1,3-dipolar cycloaddition reactions. Another type of linker, light-controlled PROTAC linker, such as photoswitch PROTAC linker, uses azo fragments instead of alkyl or polyether fragments, which causes the resulting PROTAC to undergo reversible photoisomerization when exposed to light of a specific wavelength. This enables precise and reciprocal regulation of PROTAC biodegradation rates.