Design, synthesis, and biological evaluation of novel aminopyrimidine derivatives as EGFR inhibitors

  • Bioorg Med Chem Lett. 2025 Jul 1:122:130188. doi: 10.1016/j.bmcl.2025.130188.
Huabing Wang  1 ,  Yule Gui  1 ,  Shengkai Cui  1 ,  Xinyi Long  1 ,  Weizheng Fan  1 ,  Chunlei Tang  2
Affiliations
  • 1. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China.
  • 2. School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, China. Electronic address: [email protected].
PMID: 40089036 DOI: 10.1016/j.bmcl.2025.130188
Abstract

The treatment of non-small cell lung Cancer (NSCLC) is significantly challenged by the development of acquired resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors, such as Osimertinib, which limits their therapeutic efficacy. Using the EGFR L858R/T790M/C797S inhibitor Brigatinib as a reference compound, we designed and synthesized 24 target compounds with aminopyrimidine as the core structure. Among these, the representative compound IIB-5 demonstrated potent inhibition of EGFRL858R/T790M/C797S, achieving an IC50 value of 18.81 nM. It also exhibited strong inhibition against Ba/F3-EGFRL858R/T790M/C797S cells with an IC50 of 97.12 nM, showing a five-fold potency increase over Brigatinib. Compound IIB-5 provides a valuable reference for further research on EGFR inhibitors.

Keywords
Biological activity evaluation; Cancer; Cell cycle; Chemical synthesis; EGFR inhibitors.
Products