Epidermal Growth Factor Receptor Protein Research Articles

Abstract CT156: MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced gastric/esophageal adenocarcinoma (GEA)

Abstract The epidermal growth factor receptor (EGFR) is a known driver of cancer growth and the leucine-rich, repeat-containing, G-protein coupled receptor 5 (LGR5) is a transmembrane receptor expressed on cancer stem cells. Petosemtamab is a human, common light chain, IgG1 bispecific antibody with enhanced ADCC activity targeting EGFR and LGR5, which has shown potent antitumor activity in patient (pt)-derived xenograft models of gastric and esophageal cancer. The dose escalation part of an ongoing phase 1/2 study is completed (JCO 2021:39.3 Sup 62). In the expansion part, petosemtamab is being investigated at the RP2D (1500 mg Q2W, 4-week cycle) in pts with selected advanced solid tumors, including GEA. Primary objective (expansion): investigator-assessed ORR per RECIST 1.1. Secondary objectives: ORR, DOR, PFS (per investigator and central review), OS, and safety and tolerability. Key eligibility criteria: advanced/metastatic GEA, prior exposure to ≥2 lines of standard therapy, ECOG PS 0-1, measurable disease (RECIST 1.1), available baseline tumor biopsy. At the data cutoff date of 24 October 2022, 14 GEA pts were treated at the RP2D. Median age was 63 years (range 40-80), ECOG PS 0/1: 3/11 pts, and 79% of pts were male. Primary tumor locations were esophagus (57%), stomach (36%), and gastroesophageal junction (7%), and all were adenocarcinoma histology. Pts received a median of 3 lines of prior systemic therapy (range 1-4) including platinum-based chemotherapy (100%) and checkpoint inhibitors (14%). 3/14 pts had EGFR overexpression (H score ≥200). A median of 2 treatment cycles (range 1-24) was administered, with 1 pt continuing therapy at the cutoff. Among the 14 pts evaluable for efficacy (≥2 cycles and ≥1 postbaseline scan, or early progression) limited activity was seen, however 1 pt with tumor EGFR protein overexpression and gene copy number amplification (CNA) showed a confirmed sustained PR (67% tumor reduction; response ongoing after 24 cycles) and 3 pts had SD (1 with EGFR overexpression and gene CNA; 2 not evaluable for IHC), with tumor reductions of 2%, 17%, and 40%. Among 78 pts treated at the RP2D (escalation and all expansion cohorts; cutoff 28 November 2022), the most frequent AEs regardless of causality (all grades/G3-4) were rash (33%/0%), hypotension (26%/6%), dyspnea (26%/4%), nausea (26%/1%), dermatitis acneiform (24%/1%), blood magnesium decreased (19%/5%), erythema (19%/0%), diarrhea (19%/0%); IRRs (composite term) were reported in 74%/21% of pts, mostly at the first infusion, and all resolved. 5 pts (6%) discontinued treatment due to IRRs on Day 1. 1 esophageal cancer pt died due to unrelated G5 GI bleeding. Petosemtamab demonstrated promising clinical efficacy among patients with pretreated GEA having EGFR gene amplification and/or overexpression, with a manageable safety profile. Citation Format: Marc Díez García, Antoine Hollebecque, Rocio Garcia-Carbonero, Christiane Jungels, Elisabeth Smyth, Shumei Kato, Guillem Argilés, Carlos Gomez Martin, Marina Magin, Yu-Ming Shen, Renée de Leeuw, Mohamed Bekradda, Eduardo Pennella, Ernesto Wasserman, Viktoriya Stalbovskaya, Jeroen Lammerts van Bueren, Aline Engbers, Andrew Joe, Josep Tabernero. MCLA-158 (petosemtamab), an IgG1 bispecific antibody targeting EGFR and LGR5, in advanced gastric/esophageal adenocarcinoma (GEA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT156.

A new paradigm for epidermal growth factor receptor expression exists in PTC and NIFTP regulated by microRNAs.

Identification of molecular alterations associated with tumor behavior is necessary to guide clinical management. The 2022 WHO classification has organized the thyroid follicular cell-derived neoplasms into benign, low-risk and high-risk neoplasms, and emphasized the value of biomarkers that may provide differential diagnostic and prognostic information to avoid overtreatment of low risk neoplasms. This work aims to study the epidermal growth factor receptor (EGFR) expression, functional and spatial dynamics in relation to specific miRNAs alterations in papillary thyroid cancer (PTC) and in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) considered as models of high-risk and low-risk thyroid tumors respectively. Primary thyroid cultured cells were used for miRNA gain/loss of function and luciferase reporter assays. Paraffin embedded tissues were used for real time PCR, immuno-fluorescence stain and confocal microscopy experiments. Our results showed that in PTC, EGFR mRNA is reduced as an effect of miR-146b-5p upregulation. The EGF expression is low and the ERK pathway is inhibited. The EGFR protein high cytoplasmic expression and colocalization with the endosomal/exosomal markers, ALIX and CD63, suggest the occurrence of stress-induced EGFR internalization, accumulation in endosomal vesicles and secretion via exosomes. In NIFTP EGFR transcription is increased in association with downregulation of miR-7-5p and the EGFR/ERK pathway is active indicating dependence on the canonical EGFR pathway for growth. Downregulation of transcript level along with cytoplasmic accumulation of undegraded protein is a new pattern of EGFR regulation associated with malignancy in thyroid. Further research is needed to elucidate the intracellular trafficking defects responsible for this specific EGFR dynamic in PTC.

The Impact of Human Mammary Tumor Virus (HMTV) on the Expression of Epidermal Growth Factor Receptor (EGFR) and Death-Domain Associated Protein (DAXX) in Breast Carcinoma Tissues.

The presence and characteristics of HMTV in Iraqi breast cancer women are still unknown. Furthermore, the identification of HMTV in human breast carcinoma tissue of patients differs by country, and the factors that influence it are still unknown. In many epithelial tumor types, the EGFR and its signaling pathways outcomes are necessary for the behavior of cells and regulating their proliferation, and it has been discovered that DAXX has strong carcinogenic characteristics and could be a new treatment target. This case-control retrospective study investigated the presence of HMTV in paraffin-embedded blocks (FFPT) of tumor samples from 60 Iraqi women patients diagnosed with primary breast cancer and 20 cases of benign tumors as a control group. HMTV env sequences were identified by Real-time PCR. EGFR and DAXX expression were immun0-detected by the immuno-histochemistry technique. HMTV sequences were detected in 15 (25%) samples of malignant breast tumors and 8 (40%) samples of benign breast tumors. There was no statistically significant association between the detection of env sequences of HMTV and age, grade, hormone receptors, EGFR, or DAXX expression compared to clinicopathological characteristics. However, statistically, the data showed a highly significant difference in the Expression of EGFR between study groups, age, and histological types (P=0.0001), and a significant negative association was observed between EGFR and both Her2 and TNBC. There was a statistically significant difference between DAXX (+) and DAXX (-) in study groups (P=0.002), and it was significantly associated with age and histological types of breast cancer (P=0.031 and 0.007, respectively). No significant association was found between DAXX and EGFR, grade, Her2. TNBC of breast cancer. The current study found HMTV env sequences in breast tumors of Iraqi women, suggesting that a larger sample size is needed to illustrate the potential causative role of HMTV in the development of human breast malignancy. Moreover, a negative association was found between HMTV and DAXX and EGFR Expression.

Cassia fistula L. pod shell and leaf extracts induce cell cytotoxicity and suppress cell migration by downregulating EGFR in MCF-7 cells

Introduction: Cassia fistula Linn. (CF) is a well-known Thai medicinal plant and a source of many bioactive compounds. The present work designed to examine the anticancer effects of pod shell and leaf of CF extracts on a human breast cancer cell line via the suppression of tumor development and metastasis. The expression of an epidermal growth factor receptor (EGFR) expression was interested to explore. Methods: The in vitro anticancer activities of the CF pod shell and leaf extracts, including cell cytotoxicity, cell growth, cell migration, cell death, and reactive oxygen species (ROS) formation were evaluated using sulforhodamine B (SRB), colony forming, wound healing, and flow cytometric analysis, respectively. The EGFR protein expression was determined by western blot analysis, which is related to increased cancer cell growth and resistance to apoptosis. Results: CF pod shell and leaf extracts showed significant toxicities against MCF-7 cells and inhibited the cancer cells proliferation and migratory ability of breast cancer MCF-7 cells in concentration- and time-dependent manners. Both extracts induced late cell apoptosis and significantly generated ROS formation at a dose of 250 mg/mL. Western blotting data exhibited low levels of EGFR protein expression after treating with the extracts at a dose of 1000 mg/mL. Conclusion: CF pod shell and leaf extracts are able to reduce breast cancer cell proliferation, increase cell apoptosis, and suppress cell migration through the downregulation of EGFR expression indicating anticancer activities.

Phytochemical and biological activity profiles of Thymbra linearifolia: An exclusively native species of Libyan Green mountains

Thymbra linearifolia, a Green Mountain endemic Libyan plant species belonging to the family Lamiaceae, was investigated as the plant's first documented phytochemical and biological evaluation report.The plant is used for bronchitis, cough, asthma, and gastrointestinal ailments, including dyspepsia, colic pain, and diarrhea.The phenolic and flavonoid contents of T. linearifolia were analyzed qualitatively and quantitatively by LC-MS analysis and spectrophotometric assays. These analyses revealed the presence of 60.67 mg/g of GAE (Gallic Acid Equivalents) and 26.79 mg/g of RE (Rutin Equivalents) of the phenolics and flavonoids, respectively, in the aerial parts of the plants’ ethanolic extract. Cyanidin-3-O-rutinoside (2.26 %), pelargonidin-3-O-rutinoside (2.36 %), gallocatechin (2.94 %), taxifolin (1.22 %), kaempferol-3-O-rutinoside (0.81 %), quercetin-3-O-retinosie (1.20 %), luteolin (0.99 %), apigenin (2.0 %), dimethoxy luteolin (2.97 %), and pinobanksin-3-O-acetate (2.56 %) were detected to be the major flavonoids, whereas the syringic acid hexoside (1.38 %), and rosmarinic acid (2.54 %) were among the most abundant phenolic acids in the plant’s extract. The DPPH scavenging activity was measured at an IC50 value of 34.48 μg/mL. In addition,potential reducing, metal chelating, and free radical scavenging potentials were exhibited in the in vitro assays, i.e., ABST, ORAC, FRAP, and MC. The remarkable antioxidant activity of the plant was attributed to its phenolic and flavonoid contents. The plant extract had strong cytotoxic effects on three types of cancer cell lines, i.e., MCF-7, HepG2, and Panc-1, with IC50 values of 24.023, 22.94, and 33.30 μg/mL, respectively. Furthermore, the plant extract also exhibited cytotoxic effects greater than the standard anticancer drug, doxorubicin, against all the tested cell lines. The in-silicobinding studies also demonstrated that the phytochemical constituents of T. linearifolia have a high binding affinity against the epidermal growth factor receptor (EGFR) protein, which supported the anticancer potentials of the plant.The antimicrobial assay conducted with the well-diffusion method revealed the moderate effects of the plant’s extract against Bacillus subtilis, Staphylococcus aureus, Saccharomyces cerevisiae, and Candida albicans. However, weak antimicrobial effects were recorded against the Gram-negative bacteria, Escherichia coli, and Salmonella typhimurium. These findings corroborated the immense health benefits of the plant, and substantiatedthe medicinal value claims of the plant, which is currently under use in different forms as part of the locals’ folk-medicinal chest.

Tenascin-C affects invasiveness of EGFR-mutated lung adenocarcinoma through a putative paracrine loop

Tenascin C (TNC) is an extracellular matrix (ECM) protein and a potential biomarker affecting progression of different tumor types, such as pancreatic and lung cancer. Alternative splicing variants of TNC are known to have an impact on interaction partners like other ECM proteins or cell surface receptors, including epidermal growth factor receptor (EGFR), leading to numerous and sometimes opposite roles of TNC in tumor cell dissemination and proliferation. Only little is known about the impact of TNC on biologic characteristics of lung cancer, such as invasion and metastatic potential. In the present study, we could link an increased expression of TNC in lung adenocarcinoma (LUAD) tissues with an unfavorable clinical outcome of patients. Furthermore, we investigated the functional role of TNC in LUAD. Immunohistochemical staining of TNC revealed a significant increase of TNC levels in primary tumours and metastases compared to normal lung tissue. Additionally, a significant correlation between TNC mRNA expression and EGFR copy number and protein expression levels has been determined. Moreover, inhibition of TNC in lung fibroblasts led to reduced invasiveness of LUAD cells harboring EGFR-activating mutations and to a shorter lamellipodia perimeter and a reduced lamellipodia area on the surface of LUAD cells. This study provides the evidence that TNC expression might be a biological relevant factor in LUAD progression in an EGFR-dependent manner and that it regulates tumor cell invasion by rearrangement of the actin cytoskeleton, especially affecting lamellipodia formation.

Identifying novel and potent inhibitors of EGFR protein for the drug development against the breast cancer

The epidermal growth factor receptor (EGFR) has been shown to be extremely important in numerous signaling pathways, particularly those involved in cancer progression. Many therapeutic inhibitors, consisting of both small molecules and monoclonal antibodies, have been developed to target inflammatory, triple-negative and metastatic breast cancer. With the emergence of resistance in breast cancer treatment strategies, there is a need to develop novel drug targets that not only overcome resistance, but also exhibit low toxicity and high specificity. The work presented here focuses on the identification of new inhibitors against the EGFR protein using combined computational approaches. Using a comprehensive machine learning-based virtual screening approach complemented by other computational approaches, we identified six new molecules from the ZINC database. The gold docking score of these six novel molecules is 125.95, 125.38, 123.13, 119.71, 115.64 and 113.73, respectively, while the gold score of the control group is 120.74. In addition, we also analyzed the FEC value of these compounds and found that the values of compounds 1, 2, 3 and 4 (−61.82, −63.98, −67.98 and −63.32, respectively) were higher are than those of the control group (−61.05). Furthermore, these molecules showed highly stable RMSD plots and good interaction of hydrogen bonds. The identified inhibitors provided interesting insights for understanding the electronic, hydrophobic, steric and structural requirements for EGFR inhibitory activity. Distinguishing these novel molecules could lead to the development of new drugs useful in treating breast cancer.Communicated by Ramaswamy H. Sarma

The role of claudin 18.2 and HER-2 in pancreatic cancer outcomes.

To examine the prognostic value of claudin 18.2 (CLDN18.2) and human epidermal growth factor receptor-2 (HER-2) expression in patients with resected pancreatic ductal adenocarcinoma (PDAC). This study enrolled patients who underwent surgery and were diagnosed with PDAC at Suleyman Demirel University Hospital, Turkey between 2015 and 2019. Sixty-eight patients with resected PDAC treated at a medical oncology clinic were assessed. All patients were over the age of 18 years, underwent follow-up and treatment in our unit, and had pathology slides that we could access. Clinicopathological data were obtained from medical files, including the patients' age, sex, pathological parameters, and clinical stage according to the Eighth International Union against Cancer/American Joint Committee on Cancer. Patient survival and the period from the date of diagnosis to death were assessed in the follow-up data. There was no statistically significant difference between CLDN18.2 and HER-2 expression scores for samples and patient clinicopathological characteristics. No HER-2 expression scores of ≥2 were found in the samples. Only 25% (n = 17) of the samples had HER-2 expression scores of +1. CLDN18.2 expression was detected in 54.4% (n = 37) of the patient samples. CLDN18.2 expression scores were +1 in 30.8% (n = 21) of the patient samples, +2 in 16.2% (n = 11), and +3 in 7.4% (n = 5). When CLDN18.2 and HER-2 expression were compared, a statistically significant difference and moderate positive correlation were observed. No significant relationship between HER-2 expression and survival was observed in the survival analysis of PDAC patients; however, high CLDN18.2 expression was related to longer overall survival. Our study is the third to research CLDN18.2 expression in PDAC. HER-2 expression is low and CLDN18.2 expression is high in patients with PDAC. HER-2 expression is not related to overall survival but CLDN18.2 is related and may be used as a prognostic marker in patients with PDAC.

Small Molecule EGFR Inhibitors as Anti-Cancer Agents: Discovery, Mechanisms of Action, and Opportunities.

Epidermal growth factor receptors (EGFRs) are a class of receptor tyrosine kinase that are also called ErbB1 and HER1. EGFR tyrosine kinase activity inhibition is considered a promising therapeutic strategy for the treatment of cancer. Many small-molecule inhibitors of EGFR tyrosine kinase (EGFR-TK), from medicinally privileged molecules to commercial drugs, have been overviewed. Particular attention has been paid to the structure of the molecule and its mechanism of action if reported. Subsequent classification of the molecules under discussion has been carried out. Both natural and synthetic and reversible and irreversible EGFR-tyrosine kinase inhibitors have been discussed. Various types of cancers that are caused by overexpression of the EGFR gene, their possible molecular origins, and their natures have also been counted in this article. Because the EGFR signaling pathway controls the proliferation, growth, survival, and differentiation of cells, and the mutated EGFR gene overproduces EGFR protein, which ultimately causes several types of cancer, proper understanding of the molecular dynamics between the protein structure and its inhibitors will lead to more effective and selective EGFR-TKIs, which in turn will be able to save more lives in the battle against cancer.

Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options.

The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

Ethnomedicine claim directed in-silico prediction of epidermal growth factor receptor kinase antagonist: an untapped reservoir of prospective anticancer agents

The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) that belongs to the ErbB family and governs important cellular functions like reproduction, survival, motility, and differentiation. Overexpression, intensification, and alteration of EGFR occur in a wide range of human malignancies and are associated with tumor progression and decreased anticancer drug sensitivity. As a result, EGFR has been identified as one of the primary anticancer targets. As cancer is more likely to be poorly understood in traditional medical practices, the extrapolation of an ethnomedicine-led strategy to identifying and prioritizing anticancer medicinal plants has been questioned. Nonetheless, given the challenges of developing innovative anticancer drugs that are effective, safe, inexpensive, and widely available, ethnomedicinal studies play critical roles in identifying relevant medicinal plants that can be further investigated. This study employed pharmacophore modeling, molecular docking, and molecular dynamics simulation to develop an effective agent as an inhibitor for EGFR. The final findings revealed that the selected bioactive compound stabilized the EGFR protein. The optimum orientations of the various inhibitors was Friedelin and it was chosen and subjected, along with the FDA-approved drug, to molecular dynamics modeling to determine the molecular interaction of the medication with various mutational sites in order to deduce the suitable orientation for the inhibitors. The study also attest to the ethnomedicinal claims that ethnomedicinal plants played a huge role in anticancer drug discovery and that their exploration can change the bleak picture cancer paints in our societies today.

Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation through Activation of EGFR Signalling in Fibroblasts

The potential of recombinant human prolidase (rhPEPD) to induce wound healing in an experimental model of IL-1β-induced inflammation in human fibroblasts was studied. It was found that rhPEPD significantly increased cell proliferation and viability, as well as the expression of the epidermal growth factor receptor (EGFR) and downstream signaling proteins, such as phosphorylated PI3K, AKT, and mTOR, in the studied model. Moreover, rhPEPD upregulated the expression of the β1 integrin receptor and its downstream signaling proteins, such as p-FAK, Grb2 and p-ERK 1/2. The inhibition of EGFR signaling by gefitinib abolished rhPEPD-dependent functions in an experimental model of inflammation. Subsequent studies showed that rhPEPD augmented collagen biosynthesis in IL-1β-treated fibroblasts as well as in a wound healing model (wound closure/scratch test). Although IL-1β treatment of fibroblasts increased cell migration, rhPEPD significantly enhanced this process. This effect was accompanied by an increase in the activity of MMP-2 and MMP-9, suggesting extracellular matrix (ECM) remodeling during the inflammatory process. The data suggest that rhPEPD may play an important role in EGFR-dependent cell growth in an experimental model of inflammation in human fibroblasts, and this knowledge may be useful for further approaches to the treatment of abnormalities of wound healing and other skin diseases.

Cadmium Activates EGFR/STAT5 Signaling to Overcome Calcium Chelation and Promote Epithelial to Mesenchymal Transition.

Cadmium (Cd) is a heavy metal found in cigarette smoke, as well as in air and drinking water due to agricultural and industrial activities, and it poses a health risk to the general population. Prolonged low-dose Cd exposure via inhalation or ingestion causes lung and kidney cancers in humans and in animal models. While high doses of Cd exposure are correlated with the occupational setting and are cytotoxic, low doses of Cd are mainly correlated with exposure in the general population and induce carcinogenesis. The mechanism by which Cd-exposed cells overcome calcium chelation and induce malignant transformation remains unclear. This study examines how cells exposed to low doses of Cd survive loss of E-cadherin cell-cell adhesion via activation of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 5 (STAT5), which work to upregulate genes associated with survival and proliferation. To demonstrate the role of Cd in EGFR/STAT5 activation, we exposed two epithelial cell lines, BEAS-2B and HEK293, to two different doses (0.4 µM and 1.6 µM) of Cadmium chloride hemipentahydrate (CdCl2·2.5H2O) that are environmentally relevant to levels of Cd found in food and cigarettes for 24 h (hours) and 9 weeks (wks). When comparing cells treated with Cd with control cells, the Cd treated cells exhibited faster proliferation; therefore, we studied activation of EGFR via the STAT5 pathway using immunofluorescence (IF) for protein expression and localization and, in addition, RT-qPCR to examine changes in EGFR/STAT5 inducible genes. Our results showed an increase in EGFR and phosphorylated EGFR (p-EGFR) protein, with 1.6 µM of Cadmium having the highest expression at both 24-hour (hr) and 9-week (wk) exposures. Moreover, the IF analysis also demonstrated an increase of STAT5 and phosphorylated STAT5 (pSTAT5) in both short-term and long-term exposure, with 0.4 µM having the highest expression at 24 h. Finally, via Western blot analysis, we showed that there was a dose-dependent decrease in E-cadherin protein expression and increased N-cadherin in cells treated with low doses of Cd. These data demonstrate that epithelial cells can overcome Cd-mediated toxicity via activation of EGFR pathway to induce cell proliferation and survival and promote epithelial to mesenchymal transition.

In silico evaluation of binding interaction and ADME study of new 1,3-diazetidin-2-one derivatives with high antiproliferative activity.

A series of eight novels' 1,3-diazetidin-2-ones have been proposed to assess their potential activities. They are intended to examine antiproliferative effects through inhibition of epidermal growth factor receptor (EGFR) expression. These eight compounds strongly interact with the EGFR protein, responsible for the activity. As part of a present study, these compounds were docked to the crystal structure of the EGFR (Protein Data Bank code: 1 M17) to determine their binding affinity at the active site. Based on computer predictions, two compounds were demonstrated high scores of 80.80 and 85.89. After analyzing ADME properties, these compounds were found to have significant potential for binding. Consequently, the abilities of gefitinib, erlotinib, imatinib, and sorafenib were selected for comparison as controls. Computational methods were performed to predict the critical disposition of eight novels' 1,3-diazetidin-2-one derivatives to the EGFR. Moreover, a docking technique employing the Genetic Optimization for Ligand Docking program was conducted. Compounds 2 and 7 demonstrate a high docking peace-wise scoring function (PLP) fitness of 85.89 and 80.80, respectively. They fulfilled the Lipinski's rule, topological descriptors, and fingerprints of drug-like molecular structure keys. These compounds can be used as lead compounds to develop novel antiproliferative agents. The outcome of applying this study is novel series of 1,3-diazetidin-2-one compounds as new analogs were designed and evaluated for their antiproliferative activity with a higher potency profile and binding affinity within the active sites of EGFR.

A Pilot Genome-Wide Association Study Identifies Novel Markers of Metabolic Syndrome in Patients with Psoriasis.

Recent studies have reported that psoriasis is associated with the development of metabolic syndrome. Genome-wide association studies have been used to discover gene variant markers that occur frequently in case group in relation to specific diseases. The aim of the present study was to investigate the variants of specific genes involved in metabolic syndrome associated with psoriasis. A total of 95 psoriasis patients were recruited and divided into two groups: one with metabolic syndrome (38 patients) and the other without (57 patients). After genotyping, imputation, and quality checking, the association between the several single nucleotide polymorphisms and metabolic syndrome in psoriasis was tested, followed by gene set enrichment analysis. We found 76 gene polymorphisms that conferred an increased risk for metabolic syndrome in patients with psoriasis. Four single nucleotide polymorphisms (rs17154774 of FRMD4A, rs77498336 of GPR116, rs75949580 and rs187682251 of MAPK4) showed the strongest association between metabolic syndrome and psoriasis. The epidermal growth factor receptor protein was located at the center of the protein interactions for the gene polymorphisms. This study identified several previously unknown polymorphisms associated with metabolic syndrome in psoriasis. These results highlight the potential for future genetic studies to elucidate the development, and ultimately prevent the onset, of metabolic syndrome in patients with psoriasis.

Neuroprotective potentials of ferulic acid against intracerebral hemorrhage COVID-19 through using network pharmacology approach and molecular docking analysis

Intracerebral hemorrhage (ICH) refers to severe stroke subtype that may be life-threatening or even cause death. It is clinically observed that coronavirus disease 2019 (COVID-19) may be associated with the high mortality in ICH patients. Ferulic acid, one of the functional bioactive ingredients from medicinal herbs, has been preclinically proven with beneficial activities, including neuroprotection and anti-inflammation actions. Based on current findings, we assumed that ferulic acid may play the potentials against COVID-19 when ICH. In this study, preclinical approach including network pharmacology and molecular docking was applied to detect and identify the core targets and pharmacological mechanisms involved in ferulic acid on COVID-19 and ICH. The network pharmacology analysis identified total eleven core targets in ferulic acid and COVID-19/ICH. The molecular mechanisms of ferulic acid against COVID-19 and ICH were mostly involved in induction of antiviral activity, modulation of inflammatory reaction. Molecular docking model revealed that ferulic acid might effectively bind to epidermal growth factor receptor (EGFR) protein based on strong binding capability. Current findings reflected the preclinical pharmacological activities of ferulic acid that might use for management of COVID-19 and ICH. Although there are the limitations that are absence of experimental validation, these bioinformatic results underline that ferulic acid may exert simultaneous potentials against COVID-19 and ICH through modulating integrative mechanisms and key biotargets.

The epidermal growth factor receptor in healthy pregnancy and preeclampsia.

The epidermal growth factor receptor (EGFR) is expressed robustly in the placenta, and critical processes of pregnancy such as placental growth and trophoblast fusion are dependent on EGFR function. However, the role that aberrant EGFR signaling might play in the etiology and/or maintenance of preeclampsia (PE) remains largely unexplored. Recently, we have shown that overexpression of EGFR in cultured uterine artery endothelial cells (UAEC), which express little endogenous EGFR, remaps responsiveness away from vascular endothelial growth factor receptor (VEGFR) signaling and toward EGFR, suggesting that endothelial EGFR expression may be kept low to preserve VEGFR control of angiogenesis. Here we will consider the evidence for the possibility that the endothelial dysfunction observed in PE might in some cases result from elevation of endothelial EGFR. During pregnancy, trophoblasts are known to synthesize large amounts of EGFR protein, and the placenta regularly releases syncytiotrophoblast-derived exosomes and microparticles into the maternal circulation. Although there are no reports of elevated EGFR gene expression in preeclamptic endothelial cells, the ongoing shedding of placental vesicles into the vascular system raises the possibility that EGFR-rich vesicles might fuse with endothelium, thereby contributing to the symptoms of PE by interrupting angiogenesis and blocking pregnancy-adapted vasodilatory function.

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer.

The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA's total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA's correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.

Palladium‐catalyzed synthesis of novel pyrido[3,4‐d]pyridazin‐1(2H)‐ones as promising α‐glucosidase, α‐amylase and EGFR inhibitors along with molecular docking

AbstractA novel route has been established for the synthesis of novel pyrido[3,4‐d]pyridazin‐1(2H)‐one derivative. Synthesis of intermediate 4‐methyl‐7‐(piperazin‐1‐yl)pyrido[3,4‐d]pyridazin‐1(2H)‐one carried out in the presence of Pd(PPh3)2Cl2 catalyst. Ten novel derivatives were synthesized, isolated, and characterized by various spectroscopic techniques. All synthesized molecules were screened for in silico parameters and evaluated for α‐glucosidase and α‐amylase inhibitory assay. Furthermore, all synthesized molecules were screened for anticancer activity against human lung cell line (A549), human melanoma cell line (A375) and breast cancer (MCF‐7) cell lines and their cytotoxic effects were compared. Among the compounds, 8i showed higher inhibition than standard acarbose in the antidiabetic assay. In addition, 8 g exhibited more potency than positive control doxorubicin on lung, breast, and melanoma cancer cell lines. A molecular docking study was carried out on 1RPK and 4HJO as Epidermal growth factor receptor (EGFR) proteins.

Targeting EGFR and Monitoring Tumorigenesis of Human Lung Cancer Cells In Vitro and In Vivo Using Nanodiamond-Conjugated Specific EGFR Antibody.

Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.