Design, synthesis and antitumor activity of 4-indazolylpyrimidine derivatives as EGFR inhibitors

To overcome T790M mutation, a novel series of 4-indazolypyrimidine derivatives were developed as novel EGFR inhibitors employing a scaffold hopping drug design strategy. The biological activities of the target compounds were evaluated against two tumor cell lines (A431 and NCI-H1975), normal cell 2BS and EGFR^T790M/L858R kinase. The results indicated that the majority of the compounds exhibited promising antitumor activity and low toxicity. Specifically, compounds 4e and 4s displayed the highest efficacy, with IC₅₀ values of 0.55 μM and 0.47 μM, respectively. Moreover, compounds 4e and 4s demonstrated exceptional activity against EGFR^T790M/L858R, with IC₅₀ values of 12.04 and 28.79 nM. Additionally, further studies revealed that compounds 4e and 4s could induce apoptosis in NCI-H1975 cells and arrest the cells in the G2/M phase. Molecular docking studies revealed that compounds 4e and 4s could interact closely with EGFR. These findings lay the groundwork for further investigation of compounds 4e and 4s as potential EGFR inhibitors.