Design, synthesis and antitumour activity of pyrimidine derivatives as novel selective EGFR kinase inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Non-small cell lung cancer (NSCLC) is frequently driven by epidermal growth factor receptor (EGFR) mutations.
• Acquired resistance to third-generation EGFR inhibitors like osimertinib necessitates novel therapeutic strategies.

Purpose of the Study:

• To investigate the efficacy of compound A8 as a novel EGFR kinase inhibitor.
• To evaluate A8's activity against resistant EGFR mutations, including double (L858R/T790M) and triple (L858R/T790M/C797S) mutations.

Main Methods:

• In vitro kinase inhibition assays to determine IC50 values and selectivity.
• Antiproliferative assays using H1975 NSCLC cells.
• Cell migration, apoptosis, and cell cycle analyses to elucidate the mechanism of action.

Main Results:

• Compound A8 demonstrated 88.01% inhibition of EGFR^L858R/T790M at 0.1 μM (IC50 = 5.0 nM) with 29.5 selectivity over wild-type EGFR.
• A8 exhibited potent activity against the EGFR^{L858R/T790M/C797S} triple mutation (IC50 = 2.9 nM), outperforming osimertinib.
• A8 showed superior antiproliferative effects against H1975 cells compared to osimertinib.

Conclusions:

• Compound A8 is a potent and selective inhibitor of resistant EGFR mutations, including the challenging triple mutation.
• A8's mechanism involves inhibition of cell migration, induction of apoptosis, and cell cycle arrest.
• A8 represents a promising new structural class of EGFR kinase inhibitors for overcoming therapeutic resistance in NSCLC.