Pan-EGFR inhibitor targeting EGFR 19del, L858R/T790M and C797S triple-mutations: Design, synthesis, and
Luhong Wang1, Fei Xie2, Shujing Li3
1Faculty of Medicine, Dalian University of Technology, Liaoning Province Key Laboratory of Protein Modification and Disease, Dalian 116024, China; School of Pharmaceutical Engineering, Key Laboratory of Structure-Based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, Shenyang 110016, China.
Abstract:
Acquired resistance mediated by the EGFR C797S mutation remains a critical barrier in the treatment of non-small cell lung cancer (NSCLC), reducing the effectiveness of third-generation EGFR inhibitors that target T790M-containing mutations. In this study, novel 2,4-diarylamino pyrimidine derivatives were identified and characterized as pan-mutant EGFR tyrosine kinase inhibitors. Compound D10 potently inhibited EGFR19del/T790M/C797S mutant (IC50 = 1.19 nM) and suppressed the proliferation of Ba/F3 cells harboring EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 0.192 and 1.303 μM. D10 also showed strong effects on the proliferation of EGFR19del and EGFRL858R/T790M mutants with IC50 values of 0.69 nM and 0.242 μM, respectively. D10 exhibited over 100-fold selectivity for mutant over wild-type (WT) EGFR and displayed low toxicity to normal Ba/F3 cells. Docking study demonstrated that D10 occupied the active site of EGFR and formed important hydrogen bonds with Lys728 and Ser797. The molecular dynamics simulations indicated that the binding free energy of D10 was -31.98 kcal/mol. Mechanistic studies revealed that D10 significantly inhibited cell migration, induced apoptosis in NSCLC cells. What's more, D10 inhibited EGFR and ERK1/2 autophosphorylation. In vivo studies demonstrated that D10 exhibited antitumor efficacy in NSCLC and Ba/F3 xenograft models, with favorable pharmacokinetics (53.30 % oral bioavailability) and low toxicity.
Insights
A novel compound, D10, effectively inhibits multiple epidermal growth factor receptor (EGFR) mutations, including the C797S resistance mutation in non-small cell lung cancer (NSCLC). This pan-mutant inhibitor shows potent activity and low toxicity, offering a promising new therapeutic strategy for NSCLC patients.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Acquired resistance via EGFR C797S mutation is a major challenge in non-small cell lung cancer (NSCLC) treatment.
- Third-generation EGFR inhibitors are less effective against T790M-containing mutations.
Purpose of the Study:
- To identify and characterize novel pan-mutant EGFR tyrosine kinase inhibitors.
- To evaluate the efficacy and safety of a novel compound, D10, against various EGFR mutations.
Main Methods:
- Synthesis and characterization of 2,4-diarylamino pyrimidine derivatives.
- In vitro enzyme inhibition assays and cell proliferation assays.
- Molecular docking, molecular dynamics simulations, and in vivo xenograft studies.
Main Results:
- Compound D10 potently inhibited EGFR C797S, T790M, and other mutants (IC50 as low as 1.19 nM).
- D10 demonstrated over 100-fold selectivity for mutant over wild-type EGFR with low toxicity.
- In vivo studies confirmed D10's antitumor efficacy in NSCLC xenograft models with good pharmacokinetics.
Conclusions:
- Novel 2,4-diarylamino pyrimidine derivative D10 is a potent pan-mutant EGFR inhibitor.
- D10 effectively targets EGFR mutations, including C797S, offering a potential new treatment for NSCLC.
- D10 exhibits favorable preclinical efficacy and safety profiles.
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