Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

Mansour, Mostafa A.; AboulMagd, Asmaa M.; Abbas, Samar H.; Abdel‐Rahman, Hamdy M.; Abdel‐Aziz, Mohamed

doi:10.1039/d3ra02347h

Cited by 12 publications

(3 citation statements)

References 151 publications

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“…Finally, it should be added that new fourth-generation drug candidates are emerging permanently, being representatives of different chemical classes with various mechanisms of action [ 206 ].…”

Section: Fourth Generation Of Egfr-targeted Drugsmentioning

confidence: 99%

Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

Shaban,

Kamashev,

Emelianova

et al. 2023

Cells

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Members of the EGFR family of tyrosine kinase receptors are major regulators of cellular proliferation, differentiation, and survival. In humans, abnormal activation of EGFR is associated with the development and progression of many cancer types, which makes it an attractive target for molecular-guided therapy. Two classes of EGFR-targeted cancer therapeutics include monoclonal antibodies (mAbs), which bind to the extracellular domain of EGFR, and tyrosine kinase inhibitors (TKIs), which mostly target the intracellular part of EGFR and inhibit its activity in molecular signaling. While EGFR-specific mAbs and three generations of TKIs have demonstrated clinical efficacy in various settings, molecular evolution of tumors leads to apparent and sometimes inevitable resistance to current therapeutics, which highlights the need for deeper research in this field. Here, we tried to provide a comprehensive and systematic overview of the rationale, molecular mechanisms, and clinical significance of the current EGFR-targeting drugs, highlighting potential candidate molecules in development. We summarized the underlying mechanisms of resistance and available personalized predictive approaches that may lead to improved efficacy of EGFR-targeted therapies. We also discuss recent developments and the use of specific therapeutic strategies, such as multi-targeting agents and combination therapies, for overcoming cancer resistance to EGFR-specific drugs.

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Section: Fourth Generation Of Egfr-targeted Drugsmentioning

confidence: 99%

Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

Shaban,

Kamashev,

Emelianova

et al. 2023

Cells

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“…These structures show that EGFR-TK exists in active and inactive conformers, which differ in terms of activation loop (A-loop) organization, Asp-Phe-Gly (DFG) motif, L834 and L837, and α-helix-C orientation [ 11 ]. With the aid of the X-ray structures of EGFR-TK bound to erlotinib or gefitinib, important binding interactions of quinazoline moiety to the kinase hinge region have been investigated [ 12 , 13 ]. These investigations aid in understanding the relationship between EGFR-TK and its inhibitors that is principle in developing novel target-specific kinase suppressors.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation

Radwan,

Alanazi,

Al-Dhfyan

2024

PLoS ONE

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Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics. We identified four compounds that bind to the ATP-binding region of the EGFR-TK using AutoDock 4.0 and AutoDock Vina1.1.2 and post-docking investigations. The ligand showed hydrophobic interactions to the hydrophobic region of the binding site and engaged in hydrogen bonding with Met793. The ligands also explored π–cation interactions between the π-system of the ligand–phenyl ring and the positive amino group of Lys745. Molecular mechanics Poisson–Boltzmann surface area MM/PBSA per-residue energy decomposition analyses revealed that Val726, Leu792, Met793, Gly796, Cys797, Leu798, and Thr844 contributed the most to the binding energy. Biological evaluation of the retrieved hit compounds showed suppressing activity against EGFR auto phosphorylation and selective apoptosis-induced effects toward lung cancer cells harboring the EGFR L858R/T790M double mutation. Our work anticipated into novel and specific EGFR-TKIs and identified new compounds with therapeutic potential against lung cancer.

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“…be achieved by inhibiting several PTKs. [46][47][48] Surprisingly, MM patients with the highest EGFR expression had the lowest survival rates. [49,50] Consequently, gefitinib (V), erlotinib (VI), lapatinib (VII), and afatinib (VIII) sharing the same quinazoline core as EGFR inhibitors may be especially useful as adjuncts to available standard treatments for MM patients.…”

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confidence: 99%

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

Mansour,

AboulMagd,

Abbas

et al. 2024

Archiv der Pharmazie

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Two new series of quinazoline‐chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5‐trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy‐substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)‐8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl‐2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI‐8226 cells showed that the trimethoxy‐substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc‐containing binding site of HDAC6 and HDAC8.

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Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

Abstract: Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance.

Cited by 12 publications

References 151 publications

Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications

Bioinformatics-driven discovery of novel EGFR kinase inhibitors as anti-cancer therapeutics: In silico screening and in vitro evaluation

Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma

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