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Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell
Rahul Pawara1, Iqrar Ahmad1, Deepika Nayak2
1Division of Computer-Aided Drug Design, Dept. of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, District, Dhule 425 405, Maharashtra, India.
Abstract:
T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.
Insights
New quinazoline compounds effectively inhibit T790M mutations in epidermal growth factor receptor (EGFR), overcoming resistance to EGFR tyrosine kinase inhibitors (TKIs) and showing low toxicity.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) is often mediated by the T790M mutation.
- Existing irreversible inhibitors like afatinib and dacomitinib show limited selectivity for the L858R/T790M mutant EGFR, hindering clinical use.
Purpose of the Study:
- To design and synthesize novel acrylamide-linked quinazolines as potent and selective inhibitors of EGFR T790M.
- To evaluate the anti-proliferative activity and molecular interactions of the synthesized compounds.
Main Methods:
- Synthesis of two series of novel acrylamide-linked quinazolines.
- In vitro cellular assays using gefitinib-resistant NCI-H1975 cell line to assess anti-proliferative activity.
- Molecular dynamic simulations to analyze the binding stability and interactions of compound 11h with the L858R/T790M EGFR kinase domain.
- In silico pharmacokinetic predictions and in vitro cytotoxicity assays against HepG2 cells.
Main Results:
- Compounds 2i and 11h demonstrated potent anti-proliferative activity against the NCI-H1975 cell line, with IC50 values of 0.171 µM and 0.159 µM, respectively.
- Molecular dynamic simulations confirmed the stable complex formation of compound 11h with L858R/T790M EGFR kinase domain, highlighting crucial covalent binding with Cys797.
- In silico pharmacokinetic properties for compounds 2i, 11h, and 11i were predicted to be satisfactory.
- Synthesized compounds exhibited low cytotoxicity against HepG2 cells in MTT assays.
Conclusions:
- Novel acrylamide-linked quinazolines, particularly compounds 2i and 11h, are potent and selective inhibitors of EGFR T790M.
- These compounds show promise for overcoming acquired resistance to EGFR-TKIs with favorable safety profiles.
- Further investigation into these compounds could lead to new therapeutic strategies for EGFR-mutated non-small cell lung cancer.
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