N-(Azido-PEG4)-N-Boc-PEG4-NHS ester

This PROTAC linker is designed to provide orthogonal functional handles for stepwise assembly of targeted protein degraders. It combines an azide group for bioorthogonal conjugation with a protected amine and an NHS ester for efficient coupling to lysine-bearing ligands. Its PEG-rich architecture supports aqueous solubility and flexible tethering, improving productive ternary complex formation. The following sections describe the structure and practical reactivity considerations for constructing PROTACs using this linker.

Structure: The linker is a PEG-based, flexible tether featuring an azide functionality and an NHS ester for amide bond formation, along with Boc-protected nitrogen. It contains ether linkages that confer hydrophilicity, and stable amide-forming carbonyl chemistry suitable for conjugation. Overall, it behaves as a water-compatible, conformationally adaptable spacer.

Reactivity: The NHS ester is typically activated toward nucleophilic substitution with primary amines under mildly basic aqueous buffer conditions, enabling formation of stable amide linkages to install the linker onto targeting ligands. The Boc group can be removed under standard acid-mediated deprotection to reveal an amine for further coupling. The azide enables azide–alkyne cycloaddition or related azide-based conjugation strategies, commonly using copper-free or copper-catalyzed variants depending on ligand compatibility.