Versatile Split-and-Mix Liposome PROTAC Platform for Efficient Degradation of Target Protein In Vivo.

ABSTRACT

PROTAC (Proteolysis TArgeting Chimeras) is a promising therapeutic approach for targeted protein degradation that recruits an E3 ubiquitin ligase to a specific protein of interest (POI), leading to its degradation by the proteasome. Recently, we developed a novel split-and-mix PROTAC system based on liposome self-assembly (LipoSM-PROTAC) which could achieve target protein degradation at comparable concentrations comparable to small molecules. In this study, we expanded protein targets based on the LipoSM-PROTAC platform and further examined its therapeutic effects in vivo. Notably, this platform could efficiently degrade the protein level of MEK1/2 in A375 cells or Alk in NCI-H2228 cells and display obvious tumor inhibition (60-70% inhibition rate) with negligible toxicity. This study further proved the LipoSM-PROTAC's application potentials.