Design, synthesis and biological evaluation of 2-phenylaminopyrimidine derivatives as EGFR inhibitors

  • Bioorg Med Chem Lett. 2024 Feb 6:101:129648. doi: 10.1016/j.bmcl.2024.129648.
Chunlei Tang  1 ,  Jie Wang  1 ,  Dong Wang  1 ,  Huabing Wang  1 ,  Shengkai Cui  1 ,  Tianxin Xiao  1 ,  Weizheng Fan  1 ,  Yan Zhang  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: 38331226 DOI: 10.1016/j.bmcl.2024.129648
Abstract

In the treatment of non-small cell lung Cancer (NSCLC), acquired drug resistance is a major factor that affects the efficacy of third-generation epidermal growth factor receptor (EGFR) inhibitors like Osimertinib. To overcome the L858R/T790M/C797S mutation, taking the Brigatinib as the positive control, two classes of 20 target compounds were designed and synthesized with 2-phenylaminopyrimidine as the core structure on the basis of summarizing the structure-activity relationship (SAR), following the basic principles of drug design. Representative compound I-10 potently inhibited EGFRL858R/T790M/C797S with an IC50 value of 33.26 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S cells with an IC50 value of 106.4 nM, which is 5-fold more potent than Brigatinib. Besides, the compound exhibited an inhibition rate of less than 50 % against wild-type cell (NCI-H838), which reflected its toxicity or selectivity. Furthermore, this work serves as a foundation for future studies on EGFR inhibitors.

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