The combinatorial use of two PROTACs recruiting the VHL and KEAP1 E3 ligases synergistically promotes target degradation and overcomes the hook effect.

Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. However, PROTACs are not without limitations, including suboptimal target degradation and the "hook-effect", a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation. In this study, we introduce a novel dual-PROTAC strategy utilizing two distinct E3 ligases, such as KEAP1 and VHL, to synergistically degrade KRAS(G12D) and Androgen Receptor (AR) by promoting ubiquitin chain elongation and also mitigate the hook effect. In conclusion, a dual-E3 ligase approach represents a promising avenue for optimizing PROTAC-based therapeutics.