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

  • Bioorg Med Chem Lett. 2023 Jul 15;91:129381. doi: 10.1016/j.bmcl.2023.129381.
Yu-Ze Mao  1 ,  Xiao-Xiao Xi  1 ,  Hong-Yi Zhao  1 ,  Yin-Liang Zhang  1 ,  San-Qi Zhang  2
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, PR China. Electronic address: [email protected].
PMID: 37336419 DOI: 10.1016/j.bmcl.2023.129381
Abstract

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 EGFRC797S mutation. Therefore, in order to overcome the drug resistance, we designed and synthesized a series of 2-aminopyrimidine derivatives as EGFRC797S-TKIs. Among these compounds, compounds A5 and A13 showed significant anti-proliferative activity against the KC-0116 (EGFRdel19/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 EGFRdel19/T790M/C797S. Based on these results, A5 turned out to be effective reversible EGFRC797S-TKIs which can be further developed.

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