NH-bis(PEG2-C2-acid)

designated NH-bis(PEG2-C2-acid), is engineered to provide a flexible, hydrophilic connection between a target-binding ligand and an E3-ligase recruiting module. Its PEG-based spacer and terminal carboxylic acid functionality support robust conjugation strategies that preserve solubility and facilitate productive ternary-complex formation. The structural and synthetic considerations for using this linker in PROTAC assembly are described in detail below.

Structure: The linker contains an amide-bearing nitrogen (NH) connected to two polyethylene glycol–derived segments terminated with carboxylic acid groups. It features ether linkages within the PEG units, ester/amide-compatible carbonyl functionalities, and flexible C–C and C–O bonds that enhance conformational mobility and aqueous compatibility.

Reactivity: The terminal carboxylic acids are suitable for standard PROTAC conjugation workflows via amide-bond formation, typically using coupling reagents such as carbodiimides with an activating additive to generate reactive intermediates. Reactions are commonly performed under anhydrous or low-water conditions in polar aprotic solvents with base to promote nucleophilic acyl substitution. The resulting amide linkages enable stable attachment while maintaining linker flexibility for downstream binding and degradation assays.