PEG Linkers

PEG (polyethylene glycol) linkers are hydrophilic, flexible chains widely used in medicinal chemistry to improve aqueous solubility, reduce non-specific protein binding, and enhance the pharmacokinetic profile of drug candidates. In small-molecule drug discovery, PEG linkers serve as solubilising spacers that bridge hydrophobic pharmacophores to targeting or functional groups while maintaining overall drug-likeness within acceptable molecular property space. Their low immunogenicity, conformational flexibility, and tunable chain length make them particularly valuable in the design of PROTACs and bifunctional degraders, where they connect E3 ligase ligands to target-binding warheads with sufficient reach and mobility to enable productive ternary complex formation. In Antibody-Drug Conjugates (ADCs), PEG linkers play a critical role in improving the aqueous solubility of highly hydrophobic payloads such as auristatins and maytansinoids, preventing premature aggregation of the conjugate in circulation and enabling higher drug-to-antibody ratios without compromising pharmacokinetic stability. Their incorporation between the antibody attachment point and the cleavable linker-payload unit also reduces hydrophobic interactions that can accelerate systemic clearance, thereby extending the therapeutic window of the ADC. PEG linkers are also employed to modulate membrane permeability and reduce P-glycoprotein efflux in CNS-targeted compounds, and their incorporation can mask metabolically labile groups from cytochrome P450 oxidation.

Asclera (polidocanol, Merz Aesthetics), FDA-approved in March 2010 for the treatment of uncomplicated spider veins and reticular veins of the lower extremity, is itself a PEG-based molecule: chemically defined as PEG-9 lauryl alcohol, it consists of a C12–C14 alkyl chain conjugated to an average of nine ethylene oxide units, and it is precisely this polyethylene glycol chain that confers the amphiphilic character responsible for its sclerosing mechanism, disrupting endothelial cell membranes on contact to cause vascular fibrosis and occlusion of the treated vessel. Zynlonta (loncastuximab tesirine, ADC Therapeutics), the first and only CD19-directed ADC approved by the FDA in April 2021 for relapsed or refractory diffuse large B-cell lymphoma after two or more prior lines of therapy, incorporates a monodisperse PEG8 spacer within its cleavable maleimide linker — positioned between the valine-alanine cathepsin B cleavage site and the maleimide antibody attachment point — where it solubilises the highly hydrophobic pyrrolobenzodiazepine dimer payload, prevents aggregation of the conjugate in circulation, and supports a consistent drug-to-antibody ratio of approximately two.

Our range of PEG linkers feature a range of linker lengths and incorporates a variety of synthetically tractable functional groups such as amines, carboxylic acids, ketones, hydroxyls and halogens to enable expedient synthetic strategies. In addition, functional groups to enable use in chemical biology applications can be found, such as NHS Esters for amine conjugation, azides for CuAAC or Staudinger ligation, and strained alkynes for SPAAC. Please examine a selection of PEG linkers in our catalogue. The full range can be found using our Search tools.