Other Linkers

Linkers in medicinal chemistry are structural units that connect two or more pharmacophoric domains within a molecule, playing a decisive role in determining geometry, flexibility, metabolic stability, and the overall biological profile of the conjugate or small molecule. Heterocyclic linkers, including triazoles, piperazines, piperidines, and pyrazoles, are widely employed because they offer conformational rigidity, opportunities for hydrogen bonding, and favourable contributions to solubility and selectivity that purely aliphatic or ether-based linkers cannot provide. In the context of ADCs and bifunctional molecules, linkers are broadly classified as cleavable or non-cleavable: cleavable linkers, such as the dipeptide Val-Cit (valine-citrulline) sequence, are designed to be selectively hydrolysed by lysosomal proteases such as cathepsin B upon internalisation, enabling controlled payload release specifically within tumour cells. Non-cleavable linkers, by contrast, rely on complete antibody degradation to release an active metabolite, conferring greater systemic stability and reduced off-target toxicity at the cost of payload flexibility. Val-Cit linkers have become a cornerstone of ADC design owing to their high plasma stability combined with efficient intracellular cleavage, and their incorporation has been instrumental in advancing the therapeutic index of cytotoxic payloads. In small-molecule drug discovery, heterocyclic linkers are used in PROTAC design to impose directionality on ternary complex formation, with triazole-containing linkers formed via copper-catalysed azide-alkyne cycloaddition offering a reliable and geometrically defined connection between warhead and E3 ligase ligand.

There are multiple examples of linkers in clinically approved molecules, including VEPPANU(vepdegestrant, approved 2025), a first-in-class oral PROTAC estrogen receptor degrader developed by Pfizer for ER-positive, HER2-negative metastatic breast cancer, which exemplifies the sophisticated application of linker design in targeted protein degradation, utilising a carefully optimised linker that bridges its estrogen receptor-binding domain to a cereblon E3 ligase ligand to drive potent and selective ERα degradation. Trastuzumab deruxtecan (Enhertu, approved 2019), a first-in-class HER2-directed ADC, employs a tetrapeptide-based cleavable linker that enables precise lysosomal release of its topoisomerase I inhibitor payload with a high DAR of eight. Sacituzumab govitecan (Trodelvy, approved 2020), another first-in-class ADC targeting TROP-2, utilises a hydrolysable CL2A linker incorporating a pH-sensitive carbonate bond that facilitates payload release in the mildly acidic tumour microenvironment as well as within lysosomes.

Our range of 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 linkers in our catalogue. The full range can be found using our Search tools.