Discovery of novel protein degraders based on bioorthogonal reaction-driven intracellular self-assembly strategy

Proteolysis targeting chimera (PROTAC) is a promising therapeutic modality capable of degrading undruggable proteins and overcoming the shortcomings of traditional inhibitors. However, the molecular weight and pharmaceutical properties of PROTACs fall outside of a reasonable range. To overcome the inherent poor druggability of PROTACs, an intracellular self-assembly strategy based on bio-orthogonal reaction was proposed and applied in this study. Herein, two novel classes of intracellular precursors that can self-assemble into protein degraders through bio-orthogonal reactions were explored, including a novel class of E3 ubiquitin ligase ligands bearing tetrazine (E3L-Tz) and target protein ligands incorporated with norbornene (TPL-Nb). These two types of precursors could spontaneously undergo bio-orthogonal reactions in living cells, affording novel PROTACs. Among these precursors, the biological activities of PROTACs formed by target protein ligand with norbornene group (S4N-1) were more potent than others and degrade VEGFR-2, PDGFR-β and EphB4. The results demonstrated that a highly specific bio-orthogonal reaction driven intracellular self-assembly strategy in living cells could be utilized to improve the degradation activity of PROTACs.