2. Academic Validation
  3. Targeted degradation of estrogen receptor β to overcome Osimertinib resistance in non-small cell lung carcinoma

Targeted degradation of estrogen receptor β to overcome Osimertinib resistance in non-small cell lung carcinoma

  • Bioorg Chem. 2026 Jan:168:109374. doi: 10.1016/j.bioorg.2025.109374.
Yunchong Meng 1,  Xiaofei Deng 2,  Baohua Xie 2,  Wei Lin 1,  Na Wang 3,  Xiaojun Wang 1,  Shihao Wu 1,  Chune Dong 4,  Yongde Liao 5,  Hai-Bing Zhou 6
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • 2 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
  • 4 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: cdong@whu.edu.cn.
  • 5 Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China. Electronic address: liaoyongde@hust.edu.cn.
  • 6 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology and Biosafety, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan 430071, China. Electronic address: zhouhb@whu.edu.cn.
PMID: 41401701 DOI: 10.1016/j.bioorg.2025.109374
Abstract

Osimertinib resistance remains a major challenge in advanced non-small cell lung Cancer (NSCLC) patients. Estrogen receptor β (ERβ) has been identified as a vital promoter in the emergence of Osimertinib resistance in NSCLC cells, however, the mechanism of action of ERβ underlining the development of acquired resistance to Osimertinib for NSCLC treatment remain unclear. To explore its therapeutic potential, we designed and synthesized a series of novel ERβ targeting PROteolysis Targeting Chimera (PROTAC) degraders for the first time to overcome Osimertinib resistance in NSCLC. Systematic SAR (Structure-activity relationship) study identified ERB-2 with excellent ERβ degradation activity and anti-tumor potency. Mechanistically, ERB-2-induced ERβ degradation regulates multiple cellular metabolic processes, cell cycle, and RNA translation. Noteworthily, ERB-2 could promote ROS accumulation, mitochondrial dysfunction, cell Apoptosis and restore Osimertinib sensitivity in Osimertinib-resistant NSCLC cells, eventually lead to effective reversal of Osimertinib resistance in vivo. Collectively, this study identifies ERB-2 as a potent first-in-class ERβ Degrader capable of overcoming Osimertinib resistance in NSCLC, putting forward potential solution for clinical unmet need in NSCLC treatment.

Keywords

Estrogen receptor β; NSCLC; Osimertinib resistance; PROTAC.

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