Linkers as Game-changers in PROTAC Technology: Emphasizing General Trends in PROTAC Pharmacokinetics for their Rational Design

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that act as degraders. They selectively remove disease-associated proteins by hijacking the Ubiquitin-Proteasome System (UPS). Chemically, they consist of three parts: an E3 ligase ligand, a target interest (TOI) and linker, which connects two moieties. The rapid expansion PROTAC Technology innovative therapeutic modality in cancer fostered drug discovery effort to optimize their physicochemical properties. Due large size, features far from traditional ‘drug-like’ This short review highlights some structural modifications linker component Drug Metabolism Pharmacokinetics (DMPK) profile. In particular, we discussed aspects related solubility, cell permeability, active transporters efflux and, metabolic stability.