Structural perspectives on linkers enabling cell-specific antibody-mediated targeted protein degradation
ARKIVOC, vol. 2025
Abstract
Proteolysis-targeting chimeras (PROTACs) are considered promising alternatives to conventional small molecules.PROTACs are bifunctional molecules that are separated by a spacer that brings a target protein into the proximity of E3 ubiquitin ligases, thereby mediating target protein ubiquitination and degradation through the proteasome.PROTACs are powerful due to their catalytic function, which has a strong biological effect, and they work using sub-stoichiometric concentrations, even when the binding affinity to the target protein is low.However, non-specific delivery poses substantial risks for side effects.Therefore, degrader-antibody-conjugates (DACs) have been developed as a new class of antibody-drug-conjugates (ADCs) to specifically deliver the PROTAC to the cell type of interest.In the rational design of DAC conjugates, the linker moiety has the potential to regulate many pharmacological aspects, including the mode of release, the attachment of the functional payload, the drug-antibody ratio (DAR), and the chemical properties of hydrophilicity and stability.In this minireview, we have explored which chemical linkers have been used in the DACs published to date.Finally, we provide an outlook on promising DAC linker designs aimed at further refining DAC versatility.
Authors 3
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Leiden University Medical Center
Affiliation as printed
Oncode Institute , Department of Cell and Chemical Biology , Leiden University Medical Center , Einthovenweg 20 , 2333 ZC , Leiden , the Netherlands ;
the Leiden University Medical Center , Leiden , The Netherlands ,