Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors

  • Eur J Med Chem. 2019 Feb 1:163:367-380. doi: 10.1016/j.ejmech.2018.11.069.
Bingbing Zhao  1 ,  Zhen Xiao  1 ,  Jianguo Qi  2 ,  Rong Luo  3 ,  Zhou Lan  1 ,  Yanzhuo Zhang  4 ,  Xiaohan Hu  1 ,  Qidong Tang  1 ,  Pengwu Zheng  5 ,  Shan Xu  6 ,  Wufu Zhu  7
Affiliations
  • 1. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
  • 2. Henan Provincial Key Laboratory of Natural Medicine and Immunology, Jinming Road, Kaifeng, Henan, 475004, China.
  • 3. Jiangxi Province Institute of Materia Medica, 181 East Nanjing Road, Nanchang, Jiangxi, 330000, China.
  • 4. School of Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, China.
  • 5. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: [email protected].
  • 6. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: [email protected].
  • 7. Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China. Electronic address: [email protected].
PMID: 30530173 DOI: 10.1016/j.ejmech.2018.11.069
Abstract

Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung Cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced Apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung Cancer research.

Keywords
Epidermal growth factor receptor; L858R/T790M resistance mutation; Non-small cell lung cancer; Selectivity.