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Journal Der Deutschen Dermatologischen... Jul 2023
Topics: Humans; Adenocarcinoma of Lung; Drug Eruptions; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Up-Regulation
PubMed: 37158376
DOI: 10.1111/ddg.15067 -
Pharmaceuticals (Basel, Switzerland) Apr 2023The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified... (Review)
Review
The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The quinazoline core has emerged as a favorable scaffold for the development of novel EGFR inhibitors due to increased affinity for the active site of EGFR kinase. Currently, there are five first-generation (gefitinib, erlotinib, lapatinib, vandetanib, and icotinib) and two second-generation (afatinib and dacomitinib) quinazoline-based EGFR inhibitors approved for the treatment of various types of cancers. The aim of this review is to outline the structural modulations favorable for the inhibitory activity toward both common mutant (del19 and L858R) and resistance-conferring mutant (T790M and C797S) EGFR forms, and provide an overview of the newly synthesized quinazoline derivatives as potentially competitive, covalent or allosteric inhibitors of EGFR.
PubMed: 37111291
DOI: 10.3390/ph16040534 -
Bioelectrochemistry (Amsterdam,... Aug 2023Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human...
Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human breast cancer cells is crucial for cancer diagnosis. In this work, plum-branched CdS/BiS heterostructures (CdS/BiS HSs) were synthesized under hydrothermal condition, whose photoelectrochemical (PEC) property and biocompatibility were scrutinously investigated. In parallel, a signal amplification strategy was designed based on immune recognition between epidermal growth factor receptor (EGFR) overexpressed on membrane of breast cancer cells MDA-MB-231 and its aptamer. Integration of the above together, a highly sensitive PEC cytosensor was developed for analysis of target MDA-MB-231 cells, exhibiting a wider linear range of 1 × 10 ∼ 3 × 10 cells mL with a limit of detection (LOD) down to 6 cells mL (S/N = 3). Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/BiS HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.
Topics: Humans; Female; Electrochemical Techniques; Prunus domestica; Early Detection of Cancer; Breast Neoplasms; Limit of Detection; ErbB Receptors; Biosensing Techniques
PubMed: 37060704
DOI: 10.1016/j.bioelechem.2023.108442 -
Veterinary Research Communications Dec 2023Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a...
Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a signaling molecule involving one of the epidermal growth factor receptors (EGFR), may be a promising therapeutic target. In this study, the anti-tumor effects of pan-ERBB inhibitors, which can inhibit the phosphorylation of ERBB4, were evaluated both in vitro and in vivo using a canine glioblastoma cell line. The results demonstrated that both afatinib and dacomitinib effectively reduced the expression of phosphorylated ERBB4, and significantly decreased the number of viable cells, ultimately prolonging the survival time of orthotopically xenografted mice. Further downstream of ERBB4, afatinib was found to suppress the expression of phosphorylated Akt and phosphorylated Extracellular signal-related kinases1 and 2 (ERK1/2) and induced apoptotic cell death. Thus, pan-ERBB inhibition is a promising therapeutic strategy for the treatment of canine gliomas.
Topics: Animals; Dogs; Mice; Afatinib; ErbB Receptors; Signal Transduction; Phosphorylation; Glioma; Cell Line, Tumor; Dog Diseases
PubMed: 36991174
DOI: 10.1007/s11259-023-10117-x -
Frontiers in Molecular Biosciences 2023is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, infections are the most...
is the most common cause of medical device-associated infections and is an opportunistic biofilm former. Among hospitalized patients, infections are the most prevalent, and resistant to most antibiotics. In order to overcome this resistance, it is imperative to treat the infection at a cellular level. The present study aims to identify inhibitors of the prokaryotic cell division protein FtsZ a widely conserved component of bacterial cytokinesis. Two substrate binding sites are present on the FtsZ protein; the nucleotide-binding domain and the inter-domain binding sites. Molecular modeling was used to identify potential inhibitors against the binding sites of the FtsZ protein. One hundred thirty-eight chemical entities were virtually screened for the binding sites and revealed ten molecules, each with good binding affinities (docking score range -9.549 to -4.290 kcal/mol) compared to the reference control drug, i.e., Dacomitinib (-4.450 kcal/mol) and PC190723 (-4.694 kcal/mol) at nucleotide and inter-domain binding sites respectively. These top 10 hits were further analyzed for their ADMET properties and molecular dynamics simulations. The Chloro-derivative of GTP, naphthalene-1,3-diyl bis(3,4,5-trihydroxybenzoate), Guanosine triphosphate (GTP), morpholine and methylpiperazine derivative of GTP were identified as the lead molecules for nucleotide binding site whereas for inter-domain binding site, 1-(((amino(iminio)methyl)amino)methyl)-3-(3-(tert-butyl)phenyl)-6,7-dimethoxyisoquinolin-2-ium, and Chlorogenic acidwere identified as lead molecules. Molecular dynamics simulation and post MM/GBSA analysis of the complexes revealed good protein-ligand stability predicting them as potential inhibitors of FtsZ (Figure 1). Thus, identified FtsZ inhibitors are a promising lead compounds for related infections.
PubMed: 36936991
DOI: 10.3389/fmolb.2023.1087676 -
Journal of Oncology Pharmacy Practice :... Jun 2023Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have a poor prognosis and few therapeutic... (Review)
Review
OBJECTIVE
Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have a poor prognosis and few therapeutic alternatives. We conducted a review of scientific evidence about therapies in NSCLC with EGFR exon 20 insertion mutations.
DATA SOURCES
A systematic review in PubMed® database was performed up to November 19, 2022. Clinical trials (CTs) about treatments of patients diagnosed with advanced or metastatic NSCLC harbouring EGFR exon 20 insertions who had previously received platinum-based chemotherapy were selected. CTs with a sample size of less than 10 patients were discarded. Efficacy results were used to determine the most interesting drugs. Subsequently, a more exhaustive analysis of the design of the CTs and safety of the most interesting schemes was conducted. Comparisons were attempted to develop.
DATA SUMMARY
A total of 40 records were found in the systematic search. Twelve selected CTs included the following therapies: poziotinib, osimertinib, pertuzumab-trastuzumab-docetaxel scheme, mobocertinib, amivantamab, erlotinib-onalespib regimen, luminespib, ado-trastuzumab emtansine and dacomitinib. Mobocertinib, amivantamab and poziotinib were determined as the most interesting treatments according to efficacy data. Gastrointestinal and dermatological adverse reactions were relevant in these regimens. All CTs presented a non-randomised design. No reliable comparisons could be developed.
CONCLUSIONS
The efficacy of mobocertinib, amivantamab and poziotinib in NSCLC with EGFR exon 20 insertion mutations is promising. However, therapies were assessed in single-arm CTs with low-quality evidence. Comparative studies with more extensive patient follow-up, larger sample size and better design are needed to reliably quantify the effect of these drugs.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutagenesis, Insertional; Protein Kinase Inhibitors; Mutation; ErbB Receptors; Exons
PubMed: 36916182
DOI: 10.1177/10781552231162545 -
Molecules (Basel, Switzerland) Mar 2023One of the most promising drugs recently approved for the treatment of various types of cancer is dacomitinib, which belongs to the tyrosine kinase inhibitor class. The...
One of the most promising drugs recently approved for the treatment of various types of cancer is dacomitinib, which belongs to the tyrosine kinase inhibitor class. The US Food and Drugs Administration (FDA) has recently approved dacomitinib as a first-line treatment for patients suffering from non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The current study proposes the design of a novel spectrofluorimetric method for determining dacomitinib based on newly synthesized nitrogen-doped carbon quantum dots (N-CQDs) as fluorescent probes. The proposed method is simple and does not require pretreatment or preliminary procedures. Since the studied drug does not have any fluorescent properties, the importance of the current study is magnified. When excited at 325 nm, N-CQDs exhibited native fluorescence at 417 nm, which was quantitatively and selectively quenched by the increasing concentrations of dacomitinib. The developed method involved the simple and green microwave-assisted synthesis of N-CQDs, using orange juice as a carbon source and urea as a nitrogen source. The characterization of the prepared quantum dots was performed using different spectroscopic and microscopic techniques. The synthesized dots had consistently spherical shapes and a narrow size distribution and demonstrated optimal characteristics, including a high stability and a high fluorescence quantum yield (25.3%). When assessing the effectiveness of the proposed method, several optimization factors were considered. The experiments demonstrated highly linear quenching behavior across the concentration range of 1.0-20.0 μg/mL with a correlation coefficient (r) of 0.999. The recovery percentages were found to be in the range of 98.50-100.83% and the corresponding relative standard deviation (%RSD) was 0.984. The proposed method was shown to be highly sensitive with a limit of detection (LOD) as low as 0.11 μg/mL. The type of mechanism by which quenching took place was also investigated by different means and was found to be static with a complementary inner filter effect. For quality purposes, the assessment of the validation criteria adhered to the ICHQ2(R1) recommendations. Finally, the proposed method was applied to a pharmaceutical dosage form of the drug (Vizimpro Tablets) and the obtained results were satisfactory. Considering the eco-friendly aspect of the suggested methodology, using natural materials to synthesize N-CQDs and water as a diluting solvent added to its greenness profile.
Topics: Humans; Quantum Dots; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Spectrometry, Fluorescence; Fluorescent Dyes; Carbon; Nitrogen
PubMed: 36903599
DOI: 10.3390/molecules28052351 -
Current Medicinal Chemistry 2024Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development and progression through the mechanism of tumor angiogenesis is prevalent in non-small...
Structure-based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Metabolic Reactivity Studies of Quinazoline Derivatives for their Anti-EGFR Activity Against Tumor Angiogenesis.
BACKGROUND
Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development and progression through the mechanism of tumor angiogenesis is prevalent in non-small lung cancer, head and neck cancer, cholangiocarcinoma & glioblastoma. Previous treatments targeting the oncogenic activity of EGFR's kinase domain have been hindered by acquired mutational resistance and side effects from existing drugs like erlotinib, highlighting the need for new EGFR inhibitors through structure- based drug designing.
OBJECTIVE
The research aims to develop novel quinazoline derivatives through structure-based virtual screening, molecular docking, and molecular dynamics simulation to potentially interact with EGFR's kinase domain and impede tumor angiogenic phenomenon.
METHODS
Quinazoline derivatives were retrieved and filtered from the PubChem database using structure- based virtual screening and the Lipinski rule of five drug-likeness studies. Molecular docking-based virtual screening methods and molecular dynamics simulation were then carried out to identify top leads.
RESULTS
A total of 1000 quinazoline derivatives were retrieved, with 671 compounds possessing druglike properties after applying Lipinski filters. Further filtration using ADME and toxicity filters yielded 28 compounds with good pharmacokinetic profiles. Docking-based virtual screening identified seven compounds with better binding scores than the control drug, dacomitinib. After cross-checking binding scores, three top compounds QU524, QU571, and QU297 were selected for molecular dynamics simulation study of 100 ns interval using Desmond module of Schrodinger maestro to understand their conformational stability.
CONCLUSION
The research results showed that the selected quinazoline leads exhibited better binding affinity and conformational stability than the control drug, erlotinib. These compounds also had good pharmacokinetic and pharmacodynamic profiles and did not violate Lipinski's rule of five limits. The findings suggest that these leads have the potential to target EGFR's kinase domain and inhibit the EGFR-associated phenomenon of tumor angiogenesis.
PubMed: 36892124
DOI: 10.2174/0929867330666230309143711 -
Clinical Cancer Research : An Official... Apr 2023Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or...
PURPOSE
Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.
PATIENTS AND METHODS
We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.
RESULTS
Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%).
CONCLUSIONS
We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Mutation; Prospective Studies; Protein Kinase Inhibitors; Drug Resistance, Neoplasm; Adenocarcinoma of Lung; Aniline Compounds
PubMed: 36729110
DOI: 10.1158/1078-0432.CCR-22-3484 -
Toxicology and Applied Pharmacology Feb 2023Lung cancer, the leading cause of cancer-related mortality, is the most commonly diagnosed cancer. Tyrosine kinase inhibitors (TKIs) are considered a drug-targeted...
Lung cancer, the leading cause of cancer-related mortality, is the most commonly diagnosed cancer. Tyrosine kinase inhibitors (TKIs) are considered a drug-targeted therapy for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, limited data are available involving the activity of EGFR TKIs against rare EGFR mutations. Here, based on an endogenous EGFR-depleted cell Line H3255 by CRISPR, H3255 cells with rare mutant EGFR and compound mutations EGFR were tested using cell proliferation assay, cytotoxicity, membrane potential, flow cytometry and Western blot analysis. We conducted cytotoxicity screening of EGFR mutations on six front-line TKIs based on first-, second-, and third-generation TKIs (afatinib, dacomitinib, osimertinib, erlotinib, gefitinib, and icotinib). The results showed that the sensitivity of these mutants containing rare variants EGFR to six front-line TKIs was enriched in the irreversible TKI cytotoxicity assays by determining their change in cytotoxicity, apoptosis, cell proliferation and signal pathway factors. Importantly, the variants harboring EGFR (H3255), EGFR (H3255) and EGFR (H3255) were sensitive to six TKIs and induced cytotoxicity through different pathways. Moreover, the compound mutations EGFR showed more TKI resistance than EGFR mutation and EGFR mutation. We present a comprehensive reference for the sensitivity of EGFR variants to six front-line TKIs. For patients with the EGFR S768I mutation and compound mutations EGFR, six first-line TKIs appear to be reasonable therapeutic options.
Topics: Humans; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Mutation
PubMed: 36682591
DOI: 10.1016/j.taap.2023.116385