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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent
Dou Dou1, Xingsen Zhang2, Jie Wang2
1Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China; Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China.
Abstract:
Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFRL858R/T790M/C797S with an IC50 value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFRL858R/T790M/C797S cells with the IC50 value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFRL858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFRL858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.
Insights
A new fourth-generation epidermal growth factor receptor (EGFR) inhibitor, compound 9d, effectively targets the EGFR-C797S mutation in non-small-cell lung cancer. This novel compound shows significant anti-tumor activity in preclinical models, offering potential for resistant lung cancer treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in non-small-cell lung cancer (NSCLC).
- Acquired resistance to third-generation EGFR inhibitors, particularly the EGFR-C797S mutation, poses a significant clinical challenge.
- Development of novel inhibitors is crucial to overcome treatment resistance in NSCLC.
Purpose of the Study:
- To design and synthesize novel fourth-generation EGFR inhibitors.
- To evaluate the efficacy of these inhibitors against EGFR mutations, including C797S.
- To investigate the anti-cancer potential of promising compounds in preclinical models.
Main Methods:
- Synthesis of diphenyl ether substituted quinazolin-4-amine derivatives.
- In vitro kinase activity assays against mutant EGFR (EGFRL858R/T790M/C797S).
- Cell proliferation assays in BaF3-EGFRL858R/T790M/C797S cells.
- Western blot analysis to assess EGFR phosphorylation.
- Cell cycle analysis and apoptosis assays.
- In vivo efficacy studies using a BaF3-EGFRL858R/T790M/C797S xenograft mouse model.
Main Results:
- Compound 9d demonstrated potent kinase activity against EGFRL858R/T790M/C797S (IC50 = 0.005 μM).
- 9d exhibited significant anti-proliferation effects in BaF3-EGFRL858R/T790M/C797S cells (IC50 = 0.865 μM).
- Compound 9d suppressed EGFR phosphorylation, induced apoptosis, and caused G2 cell cycle arrest in a dose-dependent manner.
- Significant tumor growth inhibition (TGI = 71.14%) was observed in the xenograft mouse model at 30 mg/kg.
Conclusions:
- Compound 9d is a promising fourth-generation EGFR inhibitor candidate.
- It effectively overcomes EGFR-C797S resistance mutations.
- Further development of 9d holds potential for treating resistant NSCLC.
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