The synthesis and evaluation of new N-(pyrazin-2-yl)-4-aminopyrimidine derivatives targeted EGFR and JAK

To discover novel active compounds against non-small cell lung Cancer, thirty one amino pyrazine derivatives were synthesized and evaluated as inhibitors against EGFR-mutation cancers. The optimal compound 14a, exhibited 15.4 nM and 18.5 nM of the IC₅₀ values against PC9 and H1975 Cancer cell lines, respectively. In H1975 xenograft nude mice, 14a exhibited 90.0 % of the TGI when oral administration at dosage of 10 mg/kg. Kinase activity assay showed that 14a not only has excellent inhibitory activity against EGFR kinase, but also has good activity against JAK2 and JAK3 kinases, exhibiting a dual target characteristics. Mechanism study indicated that 14a could inhibit the phosphorylation of EGFR protein and decrease the active form p-JAK2 for JAK2, induce an increase in intracellular ROS, which may disrupt the balance of the redox system in Cancer cells and cause the death of tumor cells. In addition, 14a could increase cellular lipid oxide MDA, meanwhile decrease GSH content, which suggests that 14a have caused Ferroptosis in Cancer cells, Finally, 14a exhibited high selectivity towards EGFR^wt cells with a selectivity ratio of 583.76, which is significant to avoid toxic side effects of drugs.

EGFR; Ferroptosis; Jak2-STAT-3 axis; Pyrazine derivatives.