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

Zhicheng Su; Tingyuan Yang; Jie Wang; Mengzhen Lai; Linjiang Tong; Gulinuer Wumaier; Zhuo Chen; Shengqing Li; Honglin Li; Hua Xie; Zhenjiang Zhao

doi:10.1016/j.bmcl.2020.127327

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. Epub 2020 Jun 9.

Authors

Zhicheng Su¹, Tingyuan Yang¹, Jie Wang¹, Mengzhen Lai², Linjiang Tong³, Gulinuer Wumaier⁴, Zhuo Chen⁵, Shengqing Li⁴, Honglin Li¹, Hua Xie⁶, Zhenjiang Zhao⁷

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: chenzhuo@ecust.edu.cn.
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: hxie@simm.ac.cn.
⁷ Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China. Electronic address: zhjzhao@ecust.edu.cn.

PMID: 32631532
DOI: 10.1016/j.bmcl.2020.127327

Abstract

The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR^{19D/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 EGFR^{19D/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/EGFR^{19D/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 EGFR^{19D/T790M/C797S} inhibitors.

Keywords: C797S; EGFR; NSCLC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
EGFR protein, human
ErbB Receptors