Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation

  • Bioorg Med Chem Lett. 2020 Aug 15;30(16):127327. doi: 10.1016/j.bmcl.2020.127327.
Zhicheng Su  1 ,  Tingyuan Yang  1 ,  Jie Wang  1 ,  Mengzhen Lai  2 ,  Linjiang Tong  3 ,  Gulinuer Wumaier  4 ,  Zhuo Chen  5 ,  Shengqing Li  4 ,  Honglin Li  1 ,  Hua Xie  6 ,  Zhenjiang Zhao  7
Affiliations
  • 1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.
  • 2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 5. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: [email protected].
  • 6. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: [email protected].
  • 7. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: [email protected].
PMID: 32631532 DOI: 10.1016/j.bmcl.2020.127327
Abstract

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR19D/T790M/C797S mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR19D/T790M/C797S (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and Apoptosis in BaF3/EGFR19D/T790M/C797S cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR19D/T790M/C797S inhibitors.

Keywords
C797S; EGFR; NSCLC.