PROTAC Linkers

PROTACs (Proteolysis Targeting Chimeric Molecules) are heterobifunctional protein degraders and promising targeted therapeutics candidates for cancer. The PROTAC linker connects two functional motifs of a PROTAC, a target protein binder and an E3 ligase recruiter.

The linker plays an important role in a PROTAC. The features of the linker (type, length, attachment position) can affect the formation of ligase:PROTAC:target ternary complex, resulting in influencing the efficient ubiquitination of the target protein and its ultimate degradation. The optimal lengths of the PROTAC linkers are reported varying from 12-carbon to over 20-carbon, and the commonly used linkers in the development of PROTACs are PEGs, Alkyl-Chain and Alkyl/ether.