NH2-PEG4-CH2COOtBu

This PEG-based PROTAC linker is designed to connect a ligand-derived warhead to an E3-recruiting moiety while providing hydrophilicity, conformational flexibility, and improved solubility in aqueous assay conditions. Its ether-rich backbone and protected carboxylate handle facilitate modular synthesis and late-stage conjugation strategies commonly used in targeted protein degradation workflows. The linker’s structure supports controlled functional-group presentation, and the following sections describe its structural features and practical reactivity for PROTAC assembly in detail below.

Structure: The linker contains a poly(ethylene glycol) ether segment terminated by a primary amine and a methylene carboxylate functionality. It features C–N and C–O ether bonds, with an ester-protected carboxylate (tert-butyl ester) that is stable under mild conditions but can be unmasked when needed.

Reactivity: The tert-butyl ester can be deprotected to reveal a carboxylic acid for amide or related coupling to activated derivatives of partner ligands. The terminal amine enables formation of urea, amide, or other nitrogen-containing linkages via standard coupling chemistries. Common approaches use acid-mediated ester cleavage, followed by carbodiimide or activated ester-mediated couplings in suitable polar organic solvents, with base and controlled pH to preserve sensitive functional groups.