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<p>Abnormal activation of fibroblast growth factor receptor 2 (FGFR2) drives tumorigenesis in various cancers. Clinical use of pan-FGFR inhibitors is limited due to emerging acquired resistance mutations within the FGFR2 kinase domain and adverse effects associated with FGFR1/4 off-target inhibition. Herein, we describe the structure-based discovery of LC-F2-1, an FGFR2-selective inhibitor that demonstrates irreversible covalent binding to the P-loop. Cellular assays confirm the high selectivity of LC-F2-1 for FGFR2 over FGFR1 and FGFR4, along with potent inhibition of FGFR2 signaling. LC-F2-1 maintains strong activity against clinically observed FGFR2 resistance variants, including gatekeeper, molecular brake, and activation loop variants. X-ray crystallography reveals conformational rearrangement of the kinase domain by LC-F2-1, which overcomes the recalcitrant V565F gatekeeper mutation. In vivo, LC-F2-1 induces tumor regression in xenograft models harboring FGFR2 resistance mutations without affecting serum phosphate levels. In this work, we identify LC-F2-1 as a therapeutic candidate for FGFR2-driven cancers.</p>

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Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Xiaohao Huang,
  • Xiansheng Cao,
  • Lulu Zheng,
  • Ruixiang Luo,
  • Zhenglan Fang,
  • Yongling Liang,
  • Yongjuan Zhu,
  • Shiyan Chen,
  • Lei Zheng,
  • Zheng Xu,
  • Xiaokun Li,
  • Guang Liang,
  • Lingfeng Chen

摘要

Abnormal activation of fibroblast growth factor receptor 2 (FGFR2) drives tumorigenesis in various cancers. Clinical use of pan-FGFR inhibitors is limited due to emerging acquired resistance mutations within the FGFR2 kinase domain and adverse effects associated with FGFR1/4 off-target inhibition. Herein, we describe the structure-based discovery of LC-F2-1, an FGFR2-selective inhibitor that demonstrates irreversible covalent binding to the P-loop. Cellular assays confirm the high selectivity of LC-F2-1 for FGFR2 over FGFR1 and FGFR4, along with potent inhibition of FGFR2 signaling. LC-F2-1 maintains strong activity against clinically observed FGFR2 resistance variants, including gatekeeper, molecular brake, and activation loop variants. X-ray crystallography reveals conformational rearrangement of the kinase domain by LC-F2-1, which overcomes the recalcitrant V565F gatekeeper mutation. In vivo, LC-F2-1 induces tumor regression in xenograft models harboring FGFR2 resistance mutations without affecting serum phosphate levels. In this work, we identify LC-F2-1 as a therapeutic candidate for FGFR2-driven cancers.