Identification of Tumor Hypoxia-Activated Degradation-Targeting Chimeras.

Targeted protein degradation (TPD) has emerged as a promising therapeutic strategy for treating cancers. Nevertheless, enhancing selectivity toward tumors remains a critical challenge. In this study, we designed and synthesized a series of hypoxia-activated degradation-targeting chimeras (HDTACs) by incorporating tumor hypoxia-activated groups (HAGs)─which generate reactive oxygen species (ROS) under tumor hypoxia conditions─into EGFR-based protein of interest (POI) ligands through appropriate linkers, leveraging the ability of ROS to induce protein degradation. Among the synthesized compounds, 11f demonstrated potent degradation of the target protein and remarkable hypoxia/normoxia selectivity in vitro, along with effective target protein degradation and significant tumor growth inhibition in vivo, thereby confirming the feasibility of the HDTAC strategy. This work presents an innovative TPD approach for cancer therapy.