Mal-PEG1-COOtBu

Mal-PEG1-COOtBu is a maleimide-terminated polyethylene glycol linker designed for efficient, site-selective conjugation in targeted protein degradation workflows. Its maleimide handle enables robust coupling to thiol-bearing ligands, while the PEG spacer supports favorable solubility and conformational flexibility that can improve PROTAC performance. This product is well-suited for assembling PROTACs by linking an E3 ligase-recruiting moiety to a warhead-bearing ligand through a stable thioether linkage. The detailed structural and reactivity considerations are provided below.

Structure: The linker features a maleimide electrophile for thiol addition and a short PEG segment that provides a hydrophilic, flexible tether. A carboxylate protected as a tert-butyl ester is present, offering stability during synthesis and enabling later deprotection. The conjugation forms a thioether at the maleimide.

Reactivity: Maleimides typically react with free thiols under mild, aqueous or mixed-solvent conditions, proceeding via a Michael-type addition to generate a stable thioether. To construct PROTACs, thiol-functionalized ligands are reacted with the maleimide linker while controlling pH to maintain thiol nucleophilicity and minimize side reactions such as hydrolysis or disulfide scrambling. Commonly used solvents include buffered aqueous media or compatible organic cosolvents; catalysts are generally not required. The tert-butyl ester can be deprotected using standard acid-mediated conditions when a carboxylate is needed for subsequent coupling steps.