Discovery of a brain-penetrant fourth-generation EGFR inhibitor to overcome the human triple (L858R/T790 M/C797S) mutation

  • Eur J Med Chem. 2025 Oct 14;302(Pt 1):118256. doi: 10.1016/j.ejmech.2025.118256.
Lei Zhao  1 ,  Yi Sheng Zhong  1 ,  Jia Chen Shi  2 ,  Peng Xie  3 ,  Guan Wang  4
Affiliations
  • 1. Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China.
  • 2. Center for Pharmacological Evaluation and Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, China.
  • 3. Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China. Electronic address: [email protected].
  • 4. Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China. Electronic address: [email protected].
PMID: 41129833 DOI: 10.1016/j.ejmech.2025.118256
Abstract

Brain metastasis remains a major challenge in lung Cancer treatment because most small-molecule targeted therapies are severely limited in their efficacy against brain metastasis by efflux transporters on the blood-brain barrier (BBB). Osimertinib has been approved as the first-line treatment for EGFR-mutated non-small cell lung Cancer (NSCLC) and exhibits good brain penetration. However, clinical resistance to Osimertinib mediated by the tertiary C797S mutation remains an unmet medical need. Here, we report a series of brigatinib derivatives, rationally designed as fourth-generation EGFR inhibitors. The representative compound D18 exhibits potent inhibitory activity against EGFRL858R/T790M/C797S, with an IC50 of 1.32 nM, and significantly inhibits the proliferation of the NCI-H1975 cell line harboring EGFRL858R/T790M/C797S, with an IC50 of 0.87 μM. In addition, compound D18 exhibits a favorable pharmacokinetic profile and excellent BBB permeability. It significantly inhibits tumor growth in the NCI-H1975 xenograft tumor model. Based on its excellent in vitro and in vivo properties, compound D18 can be considered a promising candidate for the treatment of EGFR L858R/T790M/C797S triple mutations and brain metastases.

Keywords
Antitumor; Blood-brain barrier; EGFR; NSCLC.
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