Bis-Mal-Lysine-PEG4-TFP ester

This PROTAC linker, Bis-Mal-Lysine-PEG4-TFP ester, is designed to enable efficient conjugation between lysine-targeting warheads and PEG-based spatial scaffolds, while providing a reactive handle for subsequent coupling steps. Its bis-functional architecture and PEG4 segment support controlled geometry and improved solubility, which are advantageous for building degraders that require balanced intramolecular reach. The following sections describe the linker’s structural features and practical reactivity considerations in PROTAC assembly.

Structure: The linker comprises a bis-maleimide motif and a lysine-derived component connected through a PEG4 spacer, terminating in TFP ester groups. It contains amide linkages, ether-rich PEG segments, and electrophilic ester functionalities, yielding a polar, water-compatible scaffold suitable for bioconjugation workflows.

Reactivity: TFP esters are acylating electrophiles that react with primary amines under mild, buffered conditions to form stable amide bonds, typically proceeding via nucleophilic acyl substitution. For PROTAC construction, coupling is commonly performed using amine-containing ligands (e.g., lysine residues or amine-terminated handles) in aqueous or mixed aqueous solvents, while maintaining conditions that preserve maleimide integrity. Maleimide-based steps are generally carried out with thiol nucleophiles under controlled pH to avoid premature hydrolysis.