2. Academic Validation
  3. Novel FGFR Inhibitor Combined with Radiotherapy Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death Improving Anti-Tumor Activity

Novel FGFR Inhibitor Combined with Radiotherapy Induces GSDME-Dependent Pyroptosis to Amplify Immunogenic Cell Death Improving Anti-Tumor Activity

  • J Med Chem. 2026 Jan 22;69(2):1100-1118. doi: 10.1021/acs.jmedchem.5c02321.
Xiao Li 1,  Xuejiao Song 2,  Zhanzhan Feng 1,  Guoyi Yan 3,  Qianqian Guan 4,  Shuyan Zhou 1,  Lanying Du 4,  Lidan Zhang 5,  Lifeng Zhao 4
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610000, China.
  • 3 School of Pharmacy, Xinxiang University, Xinxiang 453003, China.
  • 4 National Base for International Science and Technology Cooperation, School of Pharmacy, Chengdu University, Chengdu 610106, China.
  • 5 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610000, China.
PMID: 41467676 DOI: 10.1021/acs.jmedchem.5c02321
Abstract

Multiple preclinical and clinical studies have shown that combining Fibroblast Growth Factor receptor (FGFR) inhibitors with radiotherapy enhances antitumor efficacy. However, progress in this combination strategy remains constrained by persistent acquired resistance due to the hypoxia-induced immunosuppressive tumor microenvironment (TME). Herein, we designed and synthesized a series of dual-functional compounds by conjugating the oxygen-mimicking moiety 2-methyl-5-nitroimidazole with the FGFR Inhibitor Erdafitinib. Among these derivatives, compound 19e exhibited potent antitumor activity and radiosensitization in HCT116 and SNU-16 xenograft models. Mechanistic studies demonstrated that 19e, when combined with radiotherapy, synergistically activated the ROS-Caspase-3-GSDME axis, downregulated PD-L1 expression, and induced immunogenic cell death (ICD). These combined effects thereby enhanced tumor sensitivity to radiotherapy. Collectively, the findings support 19e as a potential therapeutic agent for the treatment of malignant tumors.

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