Identification of Tumor Hypoxia-Activated Degradation-Targeting Chimeras.

Authors

Weiyan Cheng, Ning Wang, Linnan Zhao, Shasha Li, Ruoyang Miao, Yueqin Wang, Chunxia Liu, Han Wei, Xin Tian

Published in

Journal of medicinal chemistry. Volume 69. Issue 16. Pages 19671-19689. Aug 27, 2026.

Abstract

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.

PMID:
42679150
Bibliographic data and abstract were imported from PubMed on 02 Sep 2026.

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