2. Academic Validation
  3. A Dichloropropionamide-Substituted Diaminopyrimidine EGFR-TKI Overcomes Osimertinib Resistance in NSCLC via Dual Anchoring at Ser797 and Met793

A Dichloropropionamide-Substituted Diaminopyrimidine EGFR-TKI Overcomes Osimertinib Resistance in NSCLC via Dual Anchoring at Ser797 and Met793

  • J Med Chem. 2026 Jan 8;69(1):625-659. doi: 10.1021/acs.jmedchem.5c02807.
Yuying Wang 1 2 3 4 5,  Quanwei Yu 1 2 3 6,  Xiongqi Yang 1 2 3 4 5,  Lingling Ma 1 2 3 4 5,  Ridong Huang 1 2 3 4 5,  Hai Chen 1 2 3 4 5,  Zhonghua Jiang 1 2 3 4 5,  Zhenru Wu 7,  Chengyong Wu 1 2 3,  Xuemei Deng 1 2 3,  Jing Wang 8,  Weimin Li 1 2 3 4 5,  Yang He 1 2 3 4 5
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, West China Hospital, State Key Laboratory of Respiratory Health and Multimorbidity, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 Molecularly Targeted Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4 The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan 610041, China.
  • 5 Institute of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 6 Heilongjiang Institute for Drug Control, Harbin, Heilongjiang 150088, China.
  • 7 Institute of Clinical Pathology & Department of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 8 State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100000, China.
PMID: 41428945 DOI: 10.1021/acs.jmedchem.5c02807
Abstract

The tertiary C797S mutation in the EGFR tyrosine kinase domain disrupts osimertinib binding, driving resistance in NSCLC. We designed a series of novel diaminopyrimidine derivatives to establish the interaction with Ser797. H8b potently inhibited EGFRL858R/T790M/C797S kinase with an IC50 of 3.86 nM (30-fold lower than osimertinib) and suppressed both double mutant NCI-H1975 and triple mutant H1975-M3 cells with IC50s of 0.03 μM and 0.57 μM (14- and 11-fold reductions over osimertinib, respectively). Cocrystal X-ray analysis revealed that H8b forms a "two-point tethering" in the ATP pocket with a hydrogen bond between its dichloropropionamide oxygen and Ser797, complemented by a hydrogen bond between terminal N of the piperazine ring and Phe795. Mechanistically, H8b suppressed EGFR phosphorylation and downstream Akt, STAT3, and MAPK signaling, inhibiting proliferation, invasion, and migration. In vivo, H8b achieved 71.15% tumor inhibition in H1975-M3 xenografts. This study identifies H8b as a promising EGFR-TKI overcoming C797S-mediated resistance.

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