Development of Dual-Receptor Lysosome-Targeting Chimeras for Protein Degradation.

A growing array of lysosome-targeting chimeras (LYTACs) have recently emerged as therapeutic candidates to treat malignancies and other diseases via targeted protein degradation. We established a novel dual lysosome-targeting receptor-dependent protein degradation strategy that leverages the synergistic actions of the C-X-C chemokine receptor 4 (CXCR4) and folate receptor 1 (FOLR1) to degrade extracellular and membrane proteins. Using this strategy, we developed dual-receptor lysosome-targeting chimeras to achieve efficient lysosomal degradation of programmed cell death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR). The EGFR chimera inhibited the growth of transplanted T790M-mutated drug-resistant EGFR-driven lung cancer tumors by degrading EGFR. This dual-targeting strategy exhibits significantly better protein degradation capabilities compared with single lysosome-targeting chimeras, providing a novel platform for developing drugs targeting cancer.