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Imidazo[1,2-a]quinazolines as novel, potent EGFR-TK inhibitors: Design, synthesis, bioactivity evaluation, and in
Zaman Hasanvand1, Tayebeh Oghabi Bakhshaiesh2, Fariba Peytam3
1Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Abstract:
Tyrosine protein kinases (TKs) have been proved to play substantial roles on many cellular processes and their overexpression tend to be found in various types of cancers. Therefore, over recent decades, numerous tyrosine protein kinase inhibitors particularly epidermal growth factor receptor (EGFR) inhibitors have been introduced to treat cancer. Present study describes a novel series of imidazo[1,2-a]quinazolines 18 as potential -inhibitors. These imidazoquinazolines (18a and 18o, in particular) had great anti-proliferative activities with IC50 values in the micromolar (µM) range against PC3, HepG2, HeLa, and MDA-MB-231 comparing with Erlotinib as reference marketed drug. Further evaluations on some derivatives revealed their potential to induce apoptotic cell death and cell growth arrest at G0 phase of the cell cycle. Afterwards, the kinase assay on the most potent compounds 18a and 18o demonstrated their inhibitory potencies and selectivity toward EGFR (with EGFR-IC50 values of 82.0 µM and 12.3 µM, respectively). Additionally, western blot analysis on these compounds 18a and 18o exhibited that they inhibited the phosphorylation of EGFR and its downstream molecule extracellular signal-regulated kinase (ERK1/2). However, the level of B-Actin phosphorylation was not changed. Finally, density functional theory calculations, docking study, and independent gradient model (IGM) were performed to illustrate the structure-activity relationship (SAR) and to assess the interactions between proteins and ligands. The results of molecular docking studies had great agreement with the obtained EGFR inhibitory results through in vitro evaluations.
Insights
Researchers developed novel imidazoquinazolines as potential tyrosine protein kinase inhibitors. Compounds 18a and 18o showed significant anti-cancer activity, inhibiting EGFR and inducing apoptosis, offering new therapeutic strategies.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Tyrosine protein kinases (TKs) are crucial in cellular processes and often overexpressed in cancers.
- Epidermal growth factor receptor (EGFR) inhibitors are established cancer therapeutics.
- Novel small molecules are needed to overcome resistance and improve treatment efficacy.
Purpose of the Study:
- To synthesize and evaluate a novel series of imidazo[1,2-a]quinazolines as potential tyrosine protein kinase inhibitors.
- To assess the anti-proliferative activity of these compounds against various cancer cell lines.
- To investigate the mechanism of action, including apoptosis induction, cell cycle arrest, and EGFR signaling inhibition.
Main Methods:
- Synthesis of imidazo[1,2-a]quinazoline derivatives.
- In vitro anti-proliferative assays against PC3, HepG2, HeLa, and MDA-MB-231 cell lines.
- Kinase inhibition assays, western blot analysis for signaling pathway evaluation.
- Computational studies including density functional theory, molecular docking, and IGM analysis.
Main Results:
- Compounds 18a and 18o exhibited potent anti-proliferative activity with IC50 values in the micromolar range.
- These compounds induced apoptotic cell death and cell cycle arrest at the G0 phase.
- Kinase assays confirmed EGFR inhibition (IC50: 82.0 µM for 18a, 12.3 µM for 18o) and reduced phosphorylation of EGFR and ERK1/2.
- Computational studies supported the in vitro findings regarding structure-activity relationships and protein-ligand interactions.
Conclusions:
- The novel imidazo[1,2-a]quinazoline derivatives demonstrate significant anti-cancer potential through EGFR inhibition and induction of cell death.
- Compounds 18a and 18o represent promising lead candidates for further development as EGFR-targeted cancer therapies.
- Integrated experimental and computational approaches effectively elucidated the SAR and mechanism of action.
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