2. Academic Validation
  3. Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors

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

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: zhengpw@126.com.
  • 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: shanxu9891@126.com.
  • 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: zhuwufu-1122@163.com.
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.

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