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

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 EGFR, with an IC of 1.32 nM, and significantly inhibits the proliferation of the NCI-H1975 cell line harboring EGFR, with an IC 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 triple mutations and brain metastases.