2. Academic Validation
  3. The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer

The discovery of a potent and selective third-generation EGFR kinase inhibitor as a therapy for EGFR L858R/T790M double mutant non-small cell lung cancer

  • Eur J Med Chem. 2019 Dec 1:183:111709. doi: 10.1016/j.ejmech.2019.111709.
Baijiao An 1,  Tingting Pan 1,  Jinhui Hu 2,  Yanqing Pang 3,  Ling Huang 1,  Albert S C Chan 1,  Xingshu Li 4,  Jun Yan 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 School of Biotechnology & Health Sciences, Wuyi University, Jiangmen, 529020, PR China.
  • 3 Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.
  • 4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: lixsh@mail.sysu.edu.cn.
  • 5 Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China. Electronic address: yanjun@gzucm.edu.cn.
PMID: 31581004 DOI: 10.1016/j.ejmech.2019.111709
Abstract

A new series of AZD9291 (osimertinib) derivatives containing a sulfoxide side chain at the C-4 position of an aniline moiety were designed, synthesized and evaluated. Among these derivatives, the chiral sulfoxide derivative (-)-4i exhibited excellent inhibition of EGFR kinase activity and L858R/T790M double mutant cell proliferation, with IC50 values of 4.10 nM and 10 nM, respectively. A mechanism study elucidated that (-)-4i induced cell Apoptosis and reduced phosphorylation of EGFR and Akt in a dose-dependent manner. Furthermore, (-)-4i exhibited very little apparent toxicity toward three non-tumorigenic cell lines and was less toxic than AZD9291. Moreover, the remarkable exposure (AUC0-inf: 1294.74 h ng/mL), oral bioavailability (73.69%), and relatively shorter half-life (t1/2 = 1.12 h) of (-)-4i displayed its favorable pharmacokinetic properties. Finally, the antitumor activity of (-)-4i in vivo resulted in a significant reduction of the tumor volume (TGI: 94.30%). Altogether, these results suggest that (-)-4i warrants further investigation in Non-Small cell lung Cancer (NSCLC) therapy.

Keywords

Anti-Tumor activity; Apoptosis; L858R/T790M double mutant; Non-small cell lung cancer (NSCLC); Pharmacokinetic properties.

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