Discovery of Potent and Selective Pyrrolo[2,3- d]pyrimidine Derivatives as Fourth-Generation EGFR Inhibitors Targeting Triple Mutations

  • J Med Chem. 2025 Sep 25;68(18):19205-19228. doi: 10.1021/acs.jmedchem.5c01320.
Zhenhua Wu  1  2 ,  Xueyan Liu  1  2 ,  Xiao-E Yan  3 ,  Xinyu Wu  1  2 ,  Wei Huang  3 ,  Jiajia Li  1  2 ,  Yuanming Xiu  1  2 ,  Cairui Lv  1  2 ,  Chi Sun  1  2 ,  Zheng Wang  1  2 ,  Gaoke Xu  1  2 ,  Xiaobing Wu  1  2 ,  Zhiyu Hu  1  2 ,  Huiying Huang  1  2 ,  Xin Huang  3 ,  Jianming Zhang  4 ,  Cai-Hong Yun  5 ,  Li Li  1  2 ,  Xianming Deng  1  2  6
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen 361102, China.
  • 2. State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen 361102, China.
  • 3. RedCloud Bio Co., Ltd., Taizhou 225326, China.
  • 4. Institute of Translational Medicine, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 5. Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing 100191, China.
  • 6. Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen University, Xiamen 361003, China.
PMID: 40923247 DOI: 10.1021/acs.jmedchem.5c01320
Abstract

Three generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs) have shown clinical efficacy in nonsmall cell lung Cancer (NSCLC), but acquired resistance mutations─especially the cis-EGFRT790M/C797S─remain a major challenge. Here, we report the identification of a series of pyrrolo[2,3-d]pyrimidine derivatives that inhibit C797S-mediated EGFR triple mutants. Among them, compound 31r shows subnanomolar IC50 values against Ba/F3 EGFR19del/T790M/C797S and Ba/F3 EGFRL858R/T790M/C797S, while sparing wild-type EGFR. Its binding mode with EGFR19del/T790M/C797S was revealed by a cocrystal structure, providing structural insights into its potency and selectivity. Compound 31r also displays excellent kinome selectivity and drug-like properties, including good metabolic stability (T1/2 = 5.9 h) and oral bioavailability (F = 24%). Most importantly, 31r significantly suppressed tumor growth in PC-9 EGFR19del/T790M/C797S xenograft models, achieving regression at 80 mg/kg once daily. These results highlight 31r as a promising lead compound for overcoming resistance associated with third-generation EGFR-TKIs and support its further development for drug-resistant NSCLC.

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