Design, synthesis and evaluation of new pyrimidine derivatives as EGFRC797S tyrosine kinase inhibitors

The clinical use of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung Cancer was limited by the drug resistance caused by EGFR^C797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFR^C797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFR^{del19/T790M/C797S}) cell line with high selectivity. A5 inhibited EGFR phosphorylation and induced Apoptosis of KC-0116 cell, arrested KC-0116 cell at G2/M phase. Molecular docking results showed that A5 and brigatinib bind to EGFR in a similar pattern. In addition to forming two important hydrogen bonds with Met793 residue, A5 also formed a hydrogen bond with Lys745 residues, which may play an important role for the potent inhibitory activity against EGFR^{del19/T790M/C797S}. Based on these results, A5 turned out to be effective reversible EGFR^C797S-TKIs which can be further developed.

C797S mutation; Fourth-generation EGFR tyrosine kinase inhibitors; Non-small cell lung cancer; Pyrimidine derivatives; Synthesis.