Epidermal Growth Factor Receptor Kinase Research Articles

Efficacy and Safety of Low-Dose Nab-Paclitaxel Plus Tislelizumab in Elderly Patients With Previously Treated Metastatic Non-Small Cell Lung Cancer.

The combination of immunotherapy and chemotherapy has a synergic effect in non-small cell lung cancer (NSCLC). However, the elderly are often excluded from clinical trails due to their poor health status and more comorbidities. We sought to assess the efficacy and safety of low-dose nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus tislelizumab (an anti-PD-1 antibody) in elderly patients with advanced NSCLC. In this phase 2 clinical trail, eligible patients were those aged ≥65 years with metastatic NSCLC who had disease progression after treatment with ≥1 line of chemotherapy or targeted therapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) variations were eligible if they demonstrated disease progression after treatment with ≥1 corresponding inhibitor. Primary endpoints were progression-free survival and safety/tolerability. Secondary endpoints included objective response rate and overall survival. Among 29 patients enrolled from May 2019 through August 2020, 21 (72.4%) had adenocarcinoma, 17 (58.6%) had a performance status of 2, 8 (27.6%) had asymptomatic brain metastases, and 13 (44.8%) had EGFR/ALK variations. As of the data cutoff point on April 1, 2021, median progression-free survival and overall survival were 9.5 months and 16.5 months, respectively. Ten patients achieved a partial response (objective response rate of 34.5%). Seventeen (58.6%) patients had ≥1 treatment-related adverse event, with grade 3 events seen in 3 patients (10.3%). The most common adverse events were fatigue (20.7%), fever (17.2%), abnormal liver function (17.2%), and rash (17.2%). These results suggest that low-dose nab-paclitaxel plus tislelizumab is well tolerated and effective in elderly patients with advanced NSCLC, including those with EGFR/ALK variations.

Controlled microwave-assisted reactions: A facile synthesis of polyfunctionally substituted phthalazines as dual EGFR and PI3K inhibitors in CNS SNB-75 cell line

Brain tumors are stubborn cancers with poor prognosis and disappointing survival rates. Targeted cancer therapeutics with higher efficacy and lower resistance are highly demanded. An efficient one-pot synthesis of polyfunctionalized phthalazines derivatives was developed by reacting ethyl 1-aryl-5-cyano-1,6-dihydro-4-methyl-6-oxo-3-pyridazine-carboxylates with cinnamonitrile derivatives and the cycloaddition reaction of thieno[3,4-d]pyridazines with activated double or triple bond systems under controlled microwave heating with high yields. The resultant synthesized phthalazines (5a-e, 9 and 13) were tested for their in vitro anti-cancer activities by using in vitro one dose assay at National Cancer institute, USA. Only phthalazine (5b) showed broad spectrum anti-tumor activity against most tested cancer cell lines from all subpanels with mean % GI = 22.61. Interestingly, all tested compounds showed varying growth inhibitory activity against a particular cell line, CNS SNB-75 cell line, but (5b) exhibited the highest growth inhibitory activity against CNS-SNB-75 cell line with (GI% = 108.81) and (IC50 = 3.703 ± 0.2) compared to erlotinib; (IC50 = 12.5 ± 0.68). It caused Pre-G1 apoptosis and growth arrest at S phase. It also increased percentage of the total apoptotic cells in CNS-SNB-75 cell line (39.26%) compared to control cells (2.17%) in the annexin V-FITC experiment. It revealed pronounced EGFR inhibitory activity (IC50 = 47.27 ± 2.41 ng/mL) compared to erlotinib (IC50 = 30.7 ± 1.56 ng/mL). It also inhibited the different PI3K isoforms α, β, γ and δ (with IC50 of 4.39, 13.6, 12.5 and 3.11 μg/mL, respectively compared to LY294002 (with IC50 of 12.7, 8.57, 6.89 and 5.7 μg/mL, respectively). It also caused significant lower protein expression levels of pPI3K, AKT, pAKT and Bcl2 and higher protein expression levels of BAX, Casp3 and Casp9 when compared to untreated cells. Conclusion: Phthalazine (5b) may be an effective, convenient and safe anti-cancer agent acting via proapoptotic and dual EGFR and PI3K kinase inhibitory actions in CNS SNB-75 cell line.

Gut microbiome and diet in populations with obesity: Role of the Na+/K+-ATPase transporter signaling in severe COVID-19.

The triad of obesity, a high-protein diet from animal sources, and disturbed gut microbiota have been linked to poor clinical outcomes in patients with COVID-19. In this report, the effect of oxidative stress resulting from the Na+ /K+ -ATPase transporter signaling cascade is explored as a driver of this poor clinical outcome. Protein-protein interactions with the SARS-CoV-2 proteome were identified from the interactome data for Na+ /K+ -transporting ATPase subunit α-1 (ATP1A1), epidermal growth factor receptor, and ERB-B2 receptor tyrosine kinase 2, using the curated data from the BioGRID Database of Protein Interactions. Data for the gene expression pattern of inflammatory response were from the Gene Expression Omnibus database for cardiomyocytes post SARS-CoV-2 infection (number GSE151879). The ATP1A1 subunit of the Na+ /K+ -ATPase transporter is targeted by multiple SARS-CoV-2 proteins. Furthermore, receptor proteins associated with inflammatory response, including epidermal growth factor receptor and ERB-B2 receptor tyrosine kinase 2 (which interact with ATP1A1), are also targeted by some SARS-CoV-2 proteins. This heightened interaction likely triggers a cytokine release that increases the severity of the viral infection in individuals with obesity. The similarities between the effects of SARS-CoV-2 proteins and indoxyl sulphate on the Na+ /K+ -ATPase transporter signaling cascade suggest the possibility of an augmentation of gene changes seen with COVID-19 infection that can result in a hyperinduction of cytokine release in individuals with obesity.

Glycosphingolipids in human embryonic stem cells and breast cancer stem cells, and potential cancer therapy strategies based on their structures and functions.

Expression profiles of glycosphingolipids (GSLs) in human embryonic stem cell (hESC) lines and their differentiated embryoid body (EB) outgrowth cells, consisting of three germ layers, were surveyed systematically. Several globo- and lacto-series GSLs were identified in undifferentiated hESCs and during differentiation of hESCs to EB outgrowth cells, and core structure switching of these GSLs to gangliosides was observed. Such switching was attributable to altered expression of key glycosyltransferases (GTs) in GSL biosynthetic pathways, reflecting the unique stage-specific transitions and mechanisms characteristic of the differentiation process. Lineage-specific differentiation of hESCs was associated with further GSL alterations. During differentiation of undifferentiated hESCs to neural progenitor cells, core structure switching from globo- and lacto-series to primarily gangliosides (particularly GD3) was again observed. During differentiation to endodermal cells, alterations of GSL profiles were distinct from those in differentiation to EB outgrowth or neural progenitor cells, with high expression of Gb4Cer and low expression of stage-specific embryonic antigen (SSEA)-3, -4, or GD3 in endodermal cells. Again, such profile changes resulted from alterations of key GTs in GSL biosynthetic pathways. Novel glycan structures identified on hESCs and their differentiated counterparts presumably play functional roles in hESCs and related cancer or cancer stem cells, and will be useful as surface biomarkers. We also examined GSL expression profiles in breast cancer stem cells (CSCs), using a model of epithelial-mesenchymal transition (EMT)-induced human breast CSCs. We found that GD2 and GD3, together with their common upstream GTs, GD3 synthase (GD3S) and GD2/GM2 synthase, maintained stem cell phenotype in breast CSCs. Subsequent studies showed that GD3 was associated with epidermal growth factor receptor (EGFR), and activated EGFR signaling in breast CSCs and breast cancer cell lines. GD3S knockdown enhanced cytotoxicity of gefitinib (an EGFR kinase inhibitor) in resistant MDA-MB468 cells, both in vitro and in vivo. Our findings indicate that GD3S contributes to gefitinib resistance in EGFR-positive breast cancer cells, and is a potentially useful therapeutic target in drug-resistant breast cancers.

Psorachromene induces apoptosis and suppresses tumor growth in NSCLC cells harboring EGFR L858R/T790M/C797S.

The extracts from Psoralea corylifolia Linn. (P. corylifolia) seeds have been shown to display antitumor activity. To date, the prospects of this plant and its active compounds in the treatment of non-small-cell lung cancer (NSCLC) have not been thoroughly studied. In this study, we identified a novel psorachromene compound that displays selective cytotoxic effects on all NSCLC cells tested, including NSCLC cells harboring epidermal growth factor receptor (EGFR) activation mutants (H1975L858R/T790M and H1975-MS35L858R/T790M/C797S ). Psorachromene induces G1 arrest in NSCLC cells harboring wild-type EGFR but induces apoptosis in NSCLC cells harboring activating EGFR mutations. Psorachromene inhibits activated EGFR signaling and kinase activity and suppresses tumor growth of implanted H1975-MS35L858R/T790M/C797S cells in nude mice. Molecular docking analysis revealed that psorachromene could form stronger bonds with mutant EGFR than wild-type EGFR, which might account for the greater cytotoxic effects observed in NSCLC cells harboring activating EGFR mutations (H1975 and H1975-MS35) than wild-type EGFR (A549). In conclusion, it is suggested that psorachromene is an attractive agent to be further explored for its use in the treatment of NSCLC patients harboring EGFR L858R/T790M/C797S.

The Antibiotic and Antiprotozoal Agent Dibromopropamidine Dihydrochloride is a New EGFR Inhibitor and Potential Anticancer Drug for Bladder Cancer

AbstractThe epidermal growth factor receptor (EGFR) is a promising therapeutic target in bladder cancer (BC). Thus, the development of novel EGFR inhibitor is urgently needed. We computationally screened 3,167 worldwide approved small molecule drugs for potential wild‐type EGFR inhibitors. The antibiotic and antiprotozoal agent dibromopropamidine dihydrochloride exhibited the highest cytotoxic activity in a dose‐ and time‐dependent manner, with the IC50 similar to that reported for the FDA approved EGFR inhibitors, gefitinib and higher than afatinib. We demonstrated that dibromopropamidine dihydrochloride inhibited the wild type EGFR kinase activity while had no effect on HER‐2 kinase activity. Furthermore, dibromopropamidine dihydrochloride treatment significantly promoted cell apoptosis and inhibited the phosphorylation of EGFR and its downstream proteins AKT and ERK in a dose‐dependent manner. Structural analysis of the predicted binding conformation suggested that dibromopropamidine dihydrochloride binds to EGFR at ATP binding site via the formation of two hydrogen bonds with GLY796 and ASP855. Finally, dibromopropamidine dihydrochloride significantly suppressed tumor growth in vivo. These results suggest for the first time that dibromopropamidine dihydrochloride is an EGFR inhibitor, and a promising anticancer candidate drug for the treatment of BC.

Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors.

Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR which are attractive targets for the anticancer therapy. This work aimed at designing and synthesizing 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides, western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. The molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lied at the ATP binding site of EGFR kinase domain. The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the antiproliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for the modification of pteridine-based derivatives as EGFR inhibitor.

Development of asolectin-based liposomal formulation for controlled and targeted delivery of erlotinib as a model drug for EGFR monotherapy

The present investigation was envisaged to develop liposomal formulation for efficacious and targeted delivery of epidermal growth factor receptor (EGFR) inhibitor (erlotinib) against pancreatic cancer. The marketed formulations bearing current EGFR inhibitors exhibit serious adverse effects including severe skin, hemolytic and gastrointestinal toxicity. To address the obstacles, we have developed the liposomal formulation, by ether injection method, comprising erlotinib, a tyrosine kinase EGFR inhibitor, proposed to be targeted through enhanced permeability and retention effect (EPR) effect against pancreatic cancer. On succeeding, the liposomes were characterized for various pharmaceutical attributes. The developed liposomes found to sustain a particle size of 121 ± 10.7 nm, whereas PDI of 0.22 ± 0.01 with the surface charge value of −33.7 ± 2.30 mV. The entrapment efficiency and drug loading were found to be 82.60 and 15.89 (%w/w), respectively. The hemolysis study suggested that the developed formulation was safer compared with native drug solution. The proof of concept for enhanced efficacy and decreased toxicity has been established through in vitro assays. The IC50 for free erlotinib and formulation was found to be 2.0 ± 0.3 µg/ml and 1.1 ± 0.1 µg/ml, respectively. The effectivity was evident by cellular uptake study and apoptosis, whereas cell cycle arrest study indicated that erlotinib arrests the G0/G1 phase of cell cycle. Further the erlotinib-asolectin liposomal formulation enhanced cytotoxicity in PANC-1 cells at relatively low dose, proving to be an alternative for current chemotherapeutics against pancreatic cancer.

The protective effect of safranal against intestinal tissue damage in Drosophila

Drosophila is often exposed to harmful environments, and the intestinal epithelium is the first line of defense against external infection. Intestinal stem cells (ISCs) in the Drosophila midgut play a crucial role in maintaining tissue homeostasis and compensating for cell loss caused by tissue damage. Crocus sativus L. (saffron) can protect against intestinal injury in response to inflammation; however, the specific protective components of saffron and the related mechanisms remain unclear. Safranal is one of the main components of saffron. Here, we used dextran sodium sulfate (DSS) or Erwinia carotovora carotovora 15 (Ecc15) to create an intestinal injury model and explored the protective effect of safranal against tissue damage. Excessive proliferation and differentiation of ISCs in the Drosophila midgut were observed after DSS or Ecc15 feeding; however, these phenotypes were rescued after safranal feeding. In addition, we found that this process occurred through inhibition of the c-Jun N-terminal kinase (JNK), epidermal growth factor receptor (EGFR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Furthermore, safranal inhibited the Ecc15- and DSS-induced increases in antimicrobial peptide (AMP) and reactive oxygen species (ROS) levels and intestinal epithelial cell death, thereby protecting gut integrity. In summary, safranal was found to have a significant protective effect and maintain intestinal homeostasis in Drosophila; these findings provide a foundation for the application of safranal in clinical research and the treatment of intestinal injury.

Development of penipanoid C-inspired 2-benzoyl-1-methyl-2,3-dihydroquinazolin-4(1H)-one derivatives as potential EGFR inhibitors: Synthesis, anticancer evaluation and molecular docking study

A novel class of penipanoid C-inspired 2-benzoyl-1-methyl-2,3-dihydroquinazolin-4(1H)-ones (3a-3f) and 1-methyl-2-(3,4,5-trihydroxybenzoyl)-2,3-dihydroquinazolin-4(1H)-one derivatives (10–15) was successfully synthesized using the I2/DMSO method. The newly synthesized compounds were characterized and tested for cytotoxicity against three cancer cell lines: HepG2 (human liver), MCF7 (human breast), and HCT116 (human colorectal). The majority of the tested molecules had a considerable cytotoxic impact, in some cases larger than doxorubicin. Furthermore, the inhibitory effect of six compounds (10–15) against epidermal growth factor receptor (EGFR) kinases were investigated, with three compounds (10, 11 and 12) showing good IC50 values. The IC50 values for compounds 10 and 12 against wildtype EGFR were 0.222 and 0.172 µM, respectively. Compound 12 had good enzyme inhibitory efficacy with 71.30 and 421.53 µM for the EGFR L858R and T790M mutants, respectively, which is more effective than the positive control, erlotinib, and close to lapatinib. The results of the biological screening were also confirmed by docking studies, which predicted the potential binding interactions of the target compounds with the EGFR active sites. Compounds 10 and 12 appear to be interesting lead compounds with the potential to be developed as anticancer agents, based on the findings.

Novel sulfonyl thiazolyl-hydrazone derivatives as EGFR inhibitors: Design, synthesis, biological evaluation and molecular docking studies

New hydrazonoyl-sulfonylthiazoles were designed and synthesized as EGFR inhibitors. The new sulfonylthiazole derivatives were assessed in vitro to measure their effect on EGFR. They revealed marked inhibitory activity against EGFR kinase having IC50 range from 0.037 to 0.317 μM compared to reference drug dasatinib (IC50 = 0.077 μM). Six derivatives of the newly synthesized compounds showed potent inhibitory activity relative to dasatinib. Furthermore, the new hits were examined concerning their cytotoxic effect on human breast cancer cell line (MCF7), hepatic cancer cell line (HepG2) using MTT assay. N-(2-Benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-thiazol-2-yl)-hydrazine (IC50 = 1.24 μM) revealed higher potency than dasatinib (IC50 = 11.6 μM) against MCF7cell line. Besides, N-(2-benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-5-p-tolylazo-thiazol-2-yl)-hydrazine exhibited excellent cytotoxicity against HepG2cell line (IC50 = 3.61 μM), exceeding that of dasatinib (IC50 = 14.10 μM). In addition to low cytotoxic effect on normal (WI-38) cells, describing the high safety profiles of these compounds. Moreover, molecular docking was done in order to determine the possible binding modes of such compounds inside the binding site of EGFR.

Discovery of novel rigid analogs of 2-naphthol with potent anticancer activity through multi-target topoisomerase I & II and tyrosine kinase receptor EGFR & VEGFR-2 inhibition mechanism

A novel oxygen-containing heterocyclic linked 1H-benzo[f]chromene moieties (4a-g) and (6a-g) with anti-proliferative activity against cancer cell lines was designed, synthesized, and established on the basis of spectral data. All the prepared compounds were evaluated in vitro for their anti-proliferative activity against MCF-7, HCT-116, HepG-2 cell lines and normal cell lines HFL-1, WI-38. Compounds 4a, 4b, and 6e exhibited good activity against MCF-7, HCT-116, and HepG-2 cell lines, comparable to that of Vinblastine and Doxorubicin, and weak active against normal cell lines. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds 4a, 4b, and 6e on the more sensitive cell line MCF-7 were studied. We found that compounds 4a, 4b, and 6e induce cell cycle arrest at G2/M phases for MCF-7 treated cells compared to untreated cells, which causes apoptosis and inhibits both the topoisomerase I and II enzymes. In addition, compounds 4a and 4b exhibited comparable inhibitory activity on tyrosine kinase receptors EGFR and VEGFR-2 kinases to that of the reference protein kinases inhibitor Sorafenib. The in silico molecular docking of the most active compounds into the active sites of EGFR kinase and Topo I & II enzymes provides us with a reasonable clarification of the interpreted biological data.

Phase II single-arm study of palbociclib and cetuximab rechallenge in KRAS/NRAS/BRAF wild-type (KRAS WT) metastatic colorectal cancer (mCRC) patients (pts).

88 Background: Cetuximab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is given alone or in combination with chemotherapy in the 60% of mCRC that are KRAS WT. Unfortunately, resistance inevitably develops, which may be related to downstream upregulation of the extracellular-signal-regulated kinase (ERK) pathway. Rechallenge with anti-EGFR mAb may be effective in patients previously benefiting from anti-EGFR therapy, but median progression-free survival is < 4 months, indicating need for novel more effective combinations for rechallenge. Co-inhibition of EGFR and downstream cyclin-dependent kinases 4/6 (CDK4/6) may overcome ERK pathway reactivation. We hypothesized that the addition of the CDK4/6 inhibitor palbociclib to cetuximab would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. Methods: LCCC1717 was a multicenter, single-arm, Simon’s two stage phase II study of cetuximab and palbociclib in KRAS WT mCRC treated with ≥2 prior regimens (NCT03446157). Eligible pts were enrolled to one of two cohorts depending on previous anti-EGFR mAb therapy; we report here on cohort B, which enrolled pts who had disease control for at least 4 months with anti-EGFR therapy. Cohort B was designed to initially enroll 10 evaluable pts; if ≥ 4 pts had disease control at least 4 months, then 11 more pts would be enrolled. Treatment included cetuximab 400 mg/m2 followed by 250 mg/m2 weekly, plus palbociclib 125 mg daily on days 1-21 of a 28-day cycle until progression, toxicity, or withdrawal. Primary endpoint was disease control rate (DCR) at 4 months by RECIST 1.1. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: In cohort B, 10 evaluable pts were enrolled from 2/2018-8/2020 (1 additional pt withdrew after an infusion reaction with first dose of cetuximab). Median age 59, 70% male, 90% left-sided primary. The 4-mo DCR was 2/10 (20%; 95% CI 5-52%). Given this, enrollment in this cohort was halted after first stage. Median PFS was 1.8 mo (95% CI: 1.7, NE) and median OS was 6.6 mo (95% CI: 3.6, NE). No pts had a complete or partial response; 3 pts (30%) had stable disease (SD), including 1 patient with SD for 24.7 months. The regimen was well tolerated; most common treatment-related grade 3-4 adverse events were lymphopenia (27%) and leukopenia (18%). While 55% of pts had acneiform rash, none were grade 3-4. Conclusions: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify pts likely to respond to palbociclib + cetuximab rechallenge. This emphasizes the need for screening using circulating tumor (ct) DNA of known resistance mutations to select pts for anti-EGFR rechallenge approaches. Translational work assessing ctDNA in this study is planned. Cohort A with anti-EGFR naïve patients continues enrollment. Clinical trial information: NCT03446157.

Genomic landscape and prognosis of patients with TP53-mutated non-small cell lung cancer.

BackgroundThe TP53 tumor suppressor gene plays an important role in preventing and inhibiting the growth of tumor by regulating cell cycle, apoptosis and DNA repair. Meanwhile, the TP53 gene is one of the most frequently altered gene in non-small cell lung cancer (NSCLC) patients. Mutant TP53 (TP53-MUT) may lose tumor suppressor activity and gain tumor promoting functions, which play an important role in cancer risk, therapy resistance and poor prognosis. The impact of TP53-MUT on the prognosis of NSCLC patients need to be further studied.MethodsWe obtained genomic and clinical data from The Cancer Genome Atlas (TCGA). Mutation profiles, the TMB, disease-free survival (DFS), and overall survival (OS) were compared between patients with different TP53-MUT statuses.ResultsTP53-MUTs were detected in 46.6% of patients with lung adenocarcinoma (LUAD) (264 of 566) and 82.3% of those with lung squamous cell carcinoma (LUSC) (401 of 487). The most frequently co-mutated genes in patients with LUAD carrying a TP53-MUT included classic driver genes such as epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK), while Kirsten rat sarcoma viral oncogene (KRAS) mutations and TP53-MUTs appear to be mutually exclusive. This mutual exclusivity was not observed in patients with LUSC, in whom titin (TTN) and CUB and Sushi multiple domains 3 (CSMD3) were the most frequently co-mutated genes. A higher TMB was significantly associated with TP53-MUTs in patients with LUAD but not in those with LUSC. In patients with stage I-III NSCLC who had undergone surgery, there was no significant difference in DFS between patients carrying TP53-wildtype (TP53-WT) and TP53-MUTs, irrespective of histology or mutation type. However, the presence of TP53-MUT was associated with shorter OS in patients with LUAD (49 vs. 54 months, respectively; P=0.13) and significantly longer OS in those with LUSC (62 vs. 29 months, respectively; P=0.015).ConclusionsIn contrast to most previous studies, we revealed TP53-MUT characteristic in NSCLC patients according to histology-specific differences and the association between TP53-MUT and the mutation landscape, the TMB, and the OS. These findings suggest a need for individualized management for patients with LUAD and LUSC who carry a TP53-MUT, and warrant further research.

Efficient synthesis and cytotoxic activity of polysubstituted thieno[2,3-d]pyrimidine derivatives

Thienopyrimidine scaffold is a fused heterocyclic ring system that has been found to be an integral part of pharmaceutical products to the improvement of pharmacological and biological activities. A series of polysubstituted thieno[2,3-d]pyrimidine derivatives have been synthesized and tested for their cytotoxic activity against Hela and A549 cancer cell lines in which EGFR is highly expressed. Most of the target compounds 8a-8e showed excellent activity against Hela and A549 cancer cell lines. The most promising compound 8c exhibited the similar IC50 values on A549 cell lines to the lead drug Olmutinib. The molecular docking results indicated that compound 8c bound to EGFR kinase in a different method with Olmutinib. The preliminary structure-activity relationship (SAR) suggested that the introduction of oxygen substituents was more favorable for antitumor activity. Compound 8c proved to be a promising antitumor agent.

Novel Pyridothienopyrimidine Derivatives: Design, Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents.

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC50 ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC50 ranges of 7.27–17.29 nM, higher than that of erlotinib, IC50 = 27.01 nM.

Identification of 20(S)-Ginsenoside Rh2 as a Potential EGFR Tyrosine Kinase Inhibitor.

As the main active ingredients of Panax ginseng, ginsenosides possess numerous bioactivities. Epidermal growth factor receptor (EGFR) was widely used as a valid target in anticancer therapy. Herein, the EGFR targeting activities of 20(S)-ginsenoside Rh2 (20(S)-Rh2) and the relationship of their structure-activity were investigated. Homogeneous time-resolved fluorescence assay showed that 20(S)-Rh2 significantly inhibited the activity against EGFR kinase. 20(S)-Rh2 was confirmed to effectively inhibited cell proliferation in a dose-dependent manner by MTT assay. Furthermore, quantitative real-time PCR and western blotting analysis revealed that 20(S)-Rh2 inhibited A549 cells growth via the EGFR-MAPK pathway. Meanwhile, 20(S)-Rh2 could promote cell apoptosis, block cell cycle, and reduce cell migration of A549 cells, respectively. In silico, the result suggested that both hydrophobic interactions and hydrogen-bonding interactions could contribute to stabilize their binding. Molecular dynamics simulation showed that the side chain sugar moiety of 20(S)-Rh2 was too flexible to be fixed at the active site of EGFR. Collectively, these findings suggested that 20(S)-Rh2 might serve as a potential EGFR tyrosine kinase inhibitor.

Crystal structure, Hirshfeld, computational biomolecular investigations, and MTT assay studies of amino pyrimidine derivative as EGFR kinase domain inhibitor

A nitrogen heterocyclic pyrimidine fused heterocyclic derivative 4-(4-Methoxyphenyl)-6-(2-phenylethyl)pyrimidin-2-amine (MPPPA), was synthesized and crystal structure is identified by single crystal XRD method. The asymmetric structure of MPPPA belongs to orthorhombic (Pna21) space group with unit cell parameters a = 14.6720(7) Å, b = 14.3922(6) Å, c = 7.6334(3) Å, α=β=γ= 90° and Z = 4. Two inter­molecular N3-H3A···N1i, N3-H3B···N2ii hydrogen bonds that fomrs R22(8) ring motifs in zigzag format that run along c-axis is noticed in supramolecular network of MPPPA crystal structure. The optimized structure of the compound is investigated using density functional theory (DFT). Energies of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) with other global reactivity parameters are computed. Further, surface map of molecular electrostatic potential (MEP) is determined using the electron density of the compound to recognize the reactivity region of our compound. To understand the supramolecular features, the close contacts of the molecular crystal of the complex is evaluated using Hirshfeld surface analysis by CrystalExplorer 17.5 program. Enrichment ratio is calculated to find the propensity of the intermolecular contacts in building the crystal packing. Bioactivity score, drug-likeness and ADMET properties of the compound is analysed to determine its potential bioactivity. In-silico molecular docking was performed to examine the EGFR inhibition of the MPPPA compound as a potential anticancer agent by docking with Crystal structure of EGFR kinase domain protein (PDB ID: 2J6M) using PyRx program. The MPPPA ligand is docked with 2J6M protein by three conventional N-H…O type hydrogen bonds, one C-H…O hydrogen bond, and various hydrophobic bonds with docking energy = -9.8 kcal/mol. Further, anticancer activity of MPPPA was investigated against lung cancer (A549), cervical cancer (HeLa) and liver cancer (Hep3b) cell lines and compared with activity of standard drug Gefitinib. In vitro results showed higher cytotoxicity of MPPPA with A549 cells and could be treated as lead molecule for lung cancer drug design.

Design, synthesis and structure-activity relationship studies of novel spirochromanone hydrochloride analogs as anticancer agents.

Aim: Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1-18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31μm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and ∼ two/∼fourfold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.

Design, synthesis, and molecular modeling of quinoline-based derivatives as anti-breast cancer agents targeting EGFR/AKT signaling pathway.

Two series of quinoline-thiazole and quinoline-thiazolidinone hybrids were designed, synthesized, and evaluated for their in vitro antitumor activity on MCF-7 breast cancer cell line. In comparison with lapatinib (IC50 =4.69µM), compounds 4b and 6b exhibited the best antiproliferative activity with IC50 values of 33.19 and 5.35µM, respectively. Although compound 6b showed higher cytotoxicity, compound 4b exhibited better inhibitory activity toward the epidermal growth factor receptor (EGFR) pathway than compound 6b as represented by the significant reduction in the EGFR kinase activity and the levels of phosho-EGFR and phosho-AKT when compared to lapatinib as a reference standard. Moreover, compound 4b was capable of down-regulating the anti-apoptotic genes Bcl-2 and survivin and up-regulating the level of the pro-apoptotic gene BAX. Molecular modeling study was carried out to predict the binding interactions of both compounds into the target kinase. Finally, the physicochemical properties were investigated in silico as well.