Congratulations to Thomas Geiger on a new Book Chapter published in Annual Reports in Medicinal Chemistry. Proteolysis targeting chimeras (PROTACs) are hetero-bifunctional molecules that recruit E3 ubiquitin ligases, resulting in polyubiquitination and proteasomal degradation of disease-causing proteins. PROTACs consist of a binder to an E3 ubiquitin ligase connected with a linker to a small molecule, which can recruit protein of interest. Their design makes them modular, and historically majority of the E3 or target binders were reversible small molecules. In recent years, multiple covalent approaches have been utilized in development of PROTAC molecules to leverage potential of covalent molecules to unlock novel E3 ligases as well as drug targets challenging for reversible ligands. The review discusses recent advances in covalent PROTACs, discusses their mechanism of action, with covalency on E3 ligase, target or both and presents key differences in these approaches.
You can read the full article here:
https://authors.elsevier.com/a/1k33PEz97DwLn