Thomas M. Geiger, Radosław P. Nowak
Annual Reports in Medicinal Chemistry, 2024
https://doi.org/10.1016/bs.armc.2024.10.001
Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that remove disease-causing proteins through the means of targeted protein degradation (TPD). Since their proof-of-concept over 20 years ago, PROTACs emerged as new modality in drug discovery and chemical biology. Historically, the vast majority of PROTACs use reversible-binding recruiters for both target and E3 ligase. However, in recent years more covalent PROTACs have been developed to harness the advantages of covalency such as unlocking the “undruggable” proteome to expand the repertoire of addressable targets and recruitable E3 ligases. Here, we review recent advances in covalent PROTACs, discuss their distinct mechanism of action and outline the key differences of this approach.
