Targeted protein degradation (TPD) is a promising therapeutic modality that has garnered attention in academic, industrial, and pharmaceutical research for treating diseases such as
cancer,
neurodegenerative disorders,
inflammation, and
viral infections. In this context,
proteolysis-targeting chimeras (
PROTACs) present a reliable technology for degrading disease-causing
proteins.
PROTACs complement small-molecule inhibitors, which primarily rely on direct
protein regulation. From concept-to-clinic,
PROTACs have evolved from cell impermeable
peptide molecules to orally bioavailable drugs. Despite their potential in medicinal chemistry, certain aspects regarding
PROTACs remain unclear. The clinical significance of
PROTACs is primarily limited owing to their lack of selectivity and
drug-like properties. This review focused on recently reported
PROTAC strategies, particularly in 2022. It aimed to address and overcome the challenges posed by classical
PROTACs by correlating them with emerging approaches with improved selectivity and controllability, cell permeability, linker flexibility, druggability, and
PROTAC-based approaches, developed in 2022. Furthermore, recently reported
PROTAC-based approaches are discussed, highlighting each of their advantages and limitations. We predict that several improved
PROTAC molecules will be accessible for treating patients exhibiting various conditions, including
cancer,
neurodegenerative disorders,
inflammation, and
viral infections.