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Objective: In advanced ovarian cancer, the majority of patients receive anti-angiogenic treatment with bevacizumab. However, its use is often associated with severe side effects, and not all patients benefit from the therapy. Currently, there are no reliable biomarkers to predict response to treatment. Given their role as key regulators of angiogenesis, platelet-derived growth factor receptor-beta (PDGFR-beta) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promising candidates for predictive biomarkers. This study evaluates their potential. Methods: PDGFR-beta and VEGFR-2 expression was evaluated using immunohistochemistry in a tissue microarray assay including 391 ovarian tissue samples. Correlation analyses with clinical and histopathological parameters were performed in a homogeneous cohort of 199 high grade serous ovarian cancer samples (HGSOC). Results: In HGSOC, strong stromal PDGFR-beta expression was associated with significantly shorter overall survival compared to weak/moderate expression. The impact of stromal PDGFR-beta expression on patient survival was however not restricted to the subgroup of patients receiving therapy with bevacizumab, and therefore cannot be considered as a predictive factor. For VEGFR-2, no or weak protein expression was found in the majority of the tumor samples. Survival analyses showed a more favorable prognosis with no or weak VEGFR-2 expression. Conclusions: High stromal expression levels of PDGFR-beta correlate with shorter overall survival in HGSOC. Thus, stromal PDGFR-beta might serve as a prognostic biomarker. No predictive effect in response to bevacizumab therapy could be attributed. [ABSTRACT FROM AUTHOR]

AbstractWe report the synthesis of new series of 1,3,5-triazines and 2-phenylquinazolines as anti-cancer agents. Compounds 4a-c, 5c, 5g, and 5m showed the highest cytotoxic effect against, most notably, leukemia, non-small cell lung cancer, colon carcinoma, CNS cancer, melanoma and renal cancer. The inhibitory activity against three different kinases; PI3K-α, B-Raf and VEGFR-2, was tested for the most active candidates. The tested compounds exhibited notable activity as PI3K-α inhibitors where compound 5g was found to have the highest inhibitory effect, compounds 4c and 5c showed good activities and compounds 4b and 5m had moderate activities. In B-Raf (V600E) kinase assay, compound 4b was showed the highest inhibitory activity comparable to sorafenib, while compounds 4a and 5g showed weak inhibitory effect. Regarding VEGFR-2 kinase assay, compound 4c had the best inhibitory activity compared to sorafenib, while compound 5g showed weak inhibitory effect. Molecular docking study was performed to understand the mode of binding between compounds 4b,c and 5c,m and PI3K-α, B-Raf and VEGFR-2 as target kinase enzymes. Generally, the synthesized 1,3,5-triazine derivatives were more promising anticancer agents than phenylquinazoline derivatives. The results support the fact that these compounds are worth optimizing for some new drugs in the future. [ABSTRACT FROM AUTHOR]

A new Schiff base ligand, HNMPC, was prepared and reacted with some metal ions, including Cu(II), Ni(II), Co(II), Mn(II), and VO(IV). The infrared, electronic, mass, electron spin resonance, nuclear magnetic resonance, thermal and elemental analysis, molar conductance, and magnetic susceptibility measurements were used to characterize the metal complexes. The HNMPC ligand acts as a monoanionic tridentate ONO donor in all complexes, and the coordinating sites are C=Opyridone, C=N, and the phenolate anion. All metal complexes exhibit octahedral configurations, and the results showed that the metal ion:ligand ratio was 1:2. The molecular structural parameters of the ligand and its metal complexes were determined based on the DFT level implemented in the Gaussian 09 program B3LYP/GENECP method at the 6‐311G(d,p) basis set for C, H, N, and O atoms and the SDD (Stuttgart/Dresden) basis set for the metal atoms. The theoretical data were correlated with the experimental results. Gram‐positive bacteria, Gram‐negative bacteria, yeast, and fungi were used to test the current compounds' antimicrobial activity. Investigating the antitumor activity of the ligand and its complexes against the HepG2 cell lines showed encouraging IC50 values that were on par with those of cisplatin. In order to determine the affinity and binding pattern for the synthesized compounds toward the VEGFR‐2 active site, molecular docking studies were conducted, and the results were correlated with antitumor data. Based on the obtained results, future work aimed to synthesize a new category of Schiff bases and their metal complexes derived from the current aminopyridine derivative with diverse aldehydes and ketones. [ABSTRACT FROM AUTHOR]

Abstract Targeted therapy is preferable over other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many cancer types and are considered promising targets for assigning anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a–f in ethanol containing a quantitative amount of Et2NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a–j. Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R′ = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.

The vascular endothelial growth factor receptor 2 (VEGFR2) and the hepatocyte growth factor receptor (C-Met) are critical receptors for signaling pathways controlling crucial cellular processes such as cell growth, angiogenesis and tissue regeneration. However, dysregulation of these proteins has been reported in different diseases, particularly cancer, where these proteins promote tumour growth, invasiveness, metastasis and resistance to conventional therapies. The identification of dual inhibitors targeting both VEGFR-2 and c-Met has emerged as a strategic therapeutic approach to overcome the limitations and resistance mechanisms associated with single-target therapies in clinical settings. Through molecular dynamics simulations and comparative docking analysis, we tested the inhibitory potential of 2,016 Food and Drug Administration (FDA)-approved drugs targeting VEGFR-2 and/or c-Met receptors. The results revealed that entacapone and telmisartan are potent and selective inhibitors for c-Met and VEGFR-2, respectively. Interestingly, triamterene was identified as a promising dual inhibitor, demonstrating specific and significant binding affinity to both proteins. Molecular dynamics simulations revealed key interactions between the identified compounds and critical residues in the catalytic domains of both VEGFR-2 (e.g., Lys868, Asp1028, Asp1046) and c-Met (e.g., Asp1204, His1202, Asp1222), providing insights into their mechanism of action. These findings underscore the therapeutic potential of triamterene in targeting multiple signaling pathways involved in cancer progression, metastasis and poor prognosis in patients. Our study provides a foundational framework for the development of novel anticancer compounds able to target multiple pathways in cancer. Further preclinical and clinical investigations are needed to validate the efficacy of these compounds in clinical settings and to test their ability to overcome resistance and improve patient outcome.

Abstract Background Cancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth. Methods The present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC50 of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study. Results The ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment. Conclusion The results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4. Graphical abstract

Abstract The toxicity that was caused by the developed medications for anticancer treatment is, unfortunately, an earnest problem stemming from the various involved targets, and accordingly, intense research for overcoming such a phenomenon remains indispensable. In the current inquiry, an innovative category of substituted quinazoline-based glycosides incorporating a core of 1,2,3-triazole and attached to distinct acetylated likewise deprotected sugar segments are created and produced synthetically. The resulted 1,2,3-triazolyl-glycosides products were investigated for their ability to cause cytotoxicity to several human cancer cell lines. The quinazoline based glycosyl-1,2,3-triazoles 10–13 with free hydroxy sugar moiety revealed excellent potency against (IC50 range = 5.70–8.10 µM, IC50 Doxorubicin = 5.6 ± 0.30 µM, IC50 Erlotinib = 4.3 ± 0.1 µM). against MCF-7 cancer cell line. In addition, the derived glycosides incorporating quinazolinone and triazole core 6–13 with acetylated and deprotected sugar parts showed excellent and superior potency against HCT-116 (IC50 range = 2.90–6.40 µM). The potent products were revealed as safe cytotoxic agents as indicated by their studied safety profiles. Additional research of promising candidates inhibitory analysis performed against EGFR and VEGFR-2. The hydroxylated glycosides incorporating triazole and quinazoline system 11 and 13 with N-methyl substitution of quinazolinone, gave excellent potency against EGFR (IC50 = 0.35 ± 0.11 and 0.31 ± 0.06 µM, correspondingly) since glycoside 13 revealed comparable IC50 (3.20 ± 0.15 µM) to sorafenib against VEGFR-2. For more understanding of its action mode, it was analyzed how the 1,2,3-triazolyl glycoside 13 made an effect on the apoptosis induction and the arrest of the cell cycle. It was revealed that it had the ability to stop HCT-116 cells in their cell cycle’s G1 stage. Moreover, the influence of quinazolinone-1,2,3-triazole-glycoside 13 upon p53, Bax, and Bcl-2 levels in HCT-116 units was also studied for future approaches toward its behavior. Additionally, the latter derivative may trigger apoptosis, as indicated by a significant increase in apoptotic cells. Furthermore, molecular docking was simulated to make an obvious validation and comprehension acquirement of the binding’s characteristics also attractions among the most forceful compounds side by side with their aimed enzymes.

Dual‐targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR‐2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4‐thiazolidinones/2,4‐thiazolidinediones carrying 2‐methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR‐2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR‐2 using sorafenib as a reference drug. These compounds were also evaluated against MCF‐7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, 3b (CAIX IC50 = 0.035 µM, VEGFR‐2 IC50 = 0.093 µM) and 6i (CAIX IC50 = 0.041 µM, VEGFR‐2 IC50 = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR‐2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR‐2 to comprehend the ligand‐binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR‐2 inhibitors.b [ABSTRACT FROM AUTHOR]

In this investigation, a few isoxazole derivatives have been synthesized from the cyclization of chalcone derivative with hydroxylamine hydrochloride in a basic medium using ultrasonication. The synthesized compound has been confirmed based on 1H NMR, mass spectroscopy and IR analysis. The titled compounds have been screened for their in vivo antimicrobial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Bacillus subtilis. All compounds show excellent activity against Escherichia coli and Staphylococcus aureus bacteria. Each compound has a bioavailability score of 55%, a pain assay score of zero, complies with Lipinski's rule of five, and has high gastrointestinal (GI) absorption. Compounds 3b, 3e, 4b, 4d, and 4e show the best docking scores with VEGFR-2 (PDB IDs: 4ASD, 4ASE) and Caspase-3 (PDB ID: 4QTX), ranging from -8.2 to -9.9 kcal/mol compared to standard curcumin and sorafenib. All the synthesized compounds have excellent docking scores. These compounds may thus be used as lead compounds in studies investigating VEGFR-2 and Caspase-3 inhibitors. [ABSTRACT FROM AUTHOR]

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (7a–o) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a–o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI50 values ranging from 28 to 104 nM, compared to Erlotinib (GI50 = 33 nM), and compounds 7i–m were the most potent. Compounds 7h, 7i, 7j, 7k, and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j, 7k, and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j, 7k, and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j, 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites. [ABSTRACT FROM AUTHOR]

The vascular endothelial growth factor receptor 2 (VEGFR2) and the hepatocyte growth factor receptor (C-Met) are critical receptors for signaling pathways controlling crucial cellular processes such as cell growth, angiogenesis and tissue regeneration. However, dysregulation of these proteins has been reported in different diseases, particularly cancer, where these proteins promote tumour growth, invasiveness, metastasis and resistance to conventional therapies. The identification of dual inhibitors targeting both VEGFR-2 and c-Met has emerged as a strategic therapeutic approach to overcome the limitations and resistance mechanisms associated with single-target therapies in clinical settings. Through molecular dynamics simulations and comparative docking analysis, we tested the inhibitory potential of 2,016 Food and Drug Administration (FDA)-approved drugs targeting VEGFR-2 and/or c-Met receptors. The results revealed that entacapone and telmisartan are potent and selective inhibitors for c-Met and VEGFR-2, respectively. Interestingly, triamterene was identified as a promising dual inhibitor, demonstrating specific and significant binding affinity to both proteins. Molecular dynamics simulations revealed key interactions between the identified compounds and critical residues in the catalytic domains of both VEGFR-2 (e.g., Lys868, Asp1028, Asp1046) and c-Met (e.g., Asp1204, His1202, Asp1222), providing insights into their mechanism of action. These findings underscore the therapeutic potential of triamterene in targeting multiple signaling pathways involved in cancer progression, metastasis and poor prognosis in patients. Our study provides a foundational framework for the development of novel anticancer compounds able to target multiple pathways in cancer. Further preclinical and clinical investigations are needed to validate the efficacy of these compounds in clinical settings and to test their ability to overcome resistance and improve patient outcome. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a crucial mediator of angiogenesis, playing a pivotal role in both normal physiological processes and cancer progression. Tumors harness VEGFR-2 signaling to promote abnormal blood vessel growth, which is a key step in the metastasis process, making it a valuable target for anticancer drug development. While there are VEGFR-2 inhibitors approved for therapeutic use, they face challenges like drug resistance, off-target effects, and adverse side effects, limiting their effectiveness. The quest for new drug candidates with VEGFR-2 inhibitory activity often starts with the selection of key structural motifs present in molecules currently used in clinical practice, expanding the chemical space by generating novel derivatives bearing one or more of these moieties. This review provides an overview of recent advances in the development of novel VEGFR-2 inhibitors, focusing on the synthesis of new drug candidates with promising antiproliferative and VEGFR-2 inhibition activities, organizing them by relevant structural features. [ABSTRACT FROM AUTHOR]

In this work, the biological activities of 29 novel quinazoline/phenylsulfonylfuroxan derivatives (1a–z, 1aa, 1ab, 2a, 2b, 2d, and 2f) were computationally investigated as potential anti‐cancer inhibitors against five cell lines, i.e., H1975, MCF‐7, Eca‐109, MGC‐803, and A549, which are involved in various diseases, including lung, breast, esophageal squamous carcinoma, and gastric cancer. The 2D‐QSAR predictive approach, exploiting multiple linear regression (MLR) models and rigorous internal and external cross‐validation, showed a correlation factor R2 of range: 0.68−0.82. Moreover, the MLR‐derived R2test and Y randomization (R2rand) values for the five cell lines are higher than 0.60 and less than 0.3, respectively, indicating a strong alignment with the internal and external validation data. New 70 quinazoline hybrids based on the most effective in vivo 1q inhibitor were designed, and their pIC50 activity was predicted. The best‐scoring 15 (N1–N15) compounds were further evaluated using molecular docking and dynamics simulations (100 ns) with the VEGFR‐2 kinase target (PDB code: 3U6J). All the data sets accurately predict the strongest binding affinity for the selected (N6, N7, N9, and N11) molecules, as evidenced by the highest docking score, hydrogen bond energy, and significant amino acid steric interactions. Furthermore, the RMS/RMSF/Rg dynamics parameters show that the formed complexes are satisfactorily stable. The ADMET properties indicate that the selected new ligands have shown a promising drug‐like profile and can be considered potential candidates for future anti‐cancer therapies, with perspective validating their anticancer activity by in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor is an angiogenic that promotes the development and metastasis of tumors (VEGF). The epidermal growth factor receptor, or EGFR, controls the division, growth, and death of cells via several signaling pathways. It has been found that most of the tyrosine kinase EGFR/VEGFR-2 inhibited by drugs that the FDA has approved are so far. The main objective of the present study was to identify an efficacious and selective dual inhibitor of VEGFR-2/EGFR for the treatment of cancer. Out of the 400 ligands tested against the kinases, 12 compounds demonstrated the best docking scores through molecular docking for the two kinases. Of these, only compound SCHEMBL2435814 inhibited the kinases with the highest score values when compared to a reference, vandetanib, as a dual inhibitor of EGFR/VEGFR-2 kinases through interaction with the identified active sites pocket. Following drug-likeness score toxicity and pharmacokinetic testing, the two compounds, SCHEMBL2435814 and vandetanib, were analyzed to determine how the two kinases interacted with each other. The results of calculations of π-cation interactions, hydrogen bonds, and hydrophobic interactions demonstrated a strong interaction between the two kinases and SCHEMBL2435814. Eventually, molecular dynamic modeling was used to assess the stability of complexes. This demonstrated many characteristics, including RMSF, RMSD, SASA, RG, and H-bond analysis, which demonstrated that SCHEMBL2435814 with the two kinases was more stable than vandetanib over a 100ns simulation period. By suppressing EGFR/VEGFR-2, chemical SCHEMBL2435814 may be able to postpone the signaling pathway of proteins that are essential to the advancement of cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors. [ABSTRACT FROM AUTHOR]

Background: Cancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth. Methods: The present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC50 of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study. Results: The ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment. Conclusion: The results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4. [ABSTRACT FROM AUTHOR]

IntroductionThis study investigated the tryptic hydrolysis of β-lactoglobulin (BLG) for 30, 60, 90, and 120 min at 1/200 E/S (enzyme/substrate ratio, w/w) to prepare potentially anticarcinogenic peptides.MethodsThe properties of hydrolysates were characterized, including degree of hydrolysis, free amino acids, SDS-PAGE, FTIR, and antioxidant activity employing DPPH-assay, β-carotene/linoleic acid, and FRAP assay.ResultsBLG tryptic hydrolysate produced after 60 min hydrolysis recorded the highest antioxidant activity, and LCMS analysis revealed 162 peptides of molecular masses ranging from 800 to 5671Da, most of them are of hydrophobic nature. Within the low-MW peptide group (24 peptides), there were nine hydrophobic basic (HB) and seven hydrophobic acidic (HA), representing 38% and 29%, respectively. The HB peptides may be responsible for the considerable biological activity of the hydrolysate. With dominant basic character supporting the carcinogenic activity of this hydrolysate. The in vitro anticancer activity against Mcf-7, Caco-2, and A-549 human cancer cell lines proliferation by MTT assay recorded IC50% at 42.8, 76.92, and 45.93 μg/mL, respectively. Treating each cell line with IC50% of the hydrolysate for 24 h increased the apoptosis by enhancing the expression of caspase-9 by 5.66, 7.97, and 3.28 folds over the untreated control and inhibited angiogenesis by reducing VEGFR-2 expression by about 56, 76, and 70%, respectively, indicating strong anticancer and antiangiogenic actions on human cancer cells. BLG tryptic hydrolysate may serve as a natural anticarcinogenic agent. The results of this study demonstrated that BLG hydrolysates have direct anticancer and antiangiogenic effects on human cancer cells. The chemical composition and characteristics of the BLG tryptic hydrolysate influence these biological and anticancer activities. The tryptic hydrolysates were generally effective against the three cancer cell lines studied (Mcf-7, Caco-2, and A-549). This effectiveness was assessed by measuring cell proliferation using the MTT assay and by evaluating their impact on angiogenesis through inhibition of VEGFR-2 activity.DiscussionFuture studies may focus on enhancing the anticarcinogenic effectiveness of the peptides by isolating and evaluating the most prominent individual peptide and varying the treatment conditions.

A series of novel thiazolinone derivatives have been synthesized and characterized, and their biological activities have been studied. The title compounds were synthesized by condensation of different aldehydes 11a–11e with thiosemicarbazide to give thiosemicarbazones 12a–12e, which were cyclized with ethyl bromoacetate in the presence of sodium acetate to afford new thiazolinone derivatives 13a–13e. The structure of all newly synthesized compounds was elucidated by elemental analysis and FT–IR and multinuclear NMR (1H and 13C) spectroscopy. Newly synthesized compounds 13a–13e showed weak or no antimicrobial activity against bacterial strains Escherichia coli and Staphylococcus aureus and fungal strain Candida albicans. Furthermore, the ADME properties of compounds 13a–13e were examined, and derivatives 13a and 13b but not 13c–13e were found to conform to Lipinskiʼs and Veberʼs rules without violations. The promising compounds 13a and 13b were docked against EGFR and VEGFR-2 binding sites with reduced energy scores, higher fitting, and stability. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma is a highly vascular tumor associated with vascular endothelial growth factor (VEGF) expression. The Vascular Endothelial Growth Factor -2 (VEGF-2) and its receptor was identified as a potential anti-cancer target, and it plays a crucial role in physiology as well as pathology. Inhibition of angiogenesis via blocking the signaling pathway is considered an attractive target. In the present study, 150 FDA-approved drugs have been screened using the concept of drug repurposing against VEGFR-2 by employing the molecular docking, molecular dynamics, grouping data with Machine Learning algorithms, and density functional theory (DFT) approaches. The identified compounds such as Pazopanib, Atogepant, Drosperinone, Revefenacin and Zanubrutinib shown the binding energy − 7.0 to − 9.5 kcal/mol against VEGF receptor in the molecular docking studies and have been observed as stable in the molecular dynamic simulations performed for the period of 500 ns. The MM/GBSA analysis shows that the value ranging from − 44.816 to − 82.582 kcal/mol. Harnessing the machine learning approaches revealed that clustering with K = 10 exhibits the relevance through high binding energy and satisfactory logP values, setting them apart from compounds in distinct clusters. Therefore, the identified compounds are found to be potential to inhibit the VEGFR-2 and the present study will be a benchmark to validate the compounds experimentally. [ABSTRACT FROM AUTHOR]

Abstract New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides’ cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39–16.90 μM against HepG-2 and 19.57–21.15 μM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 μM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 μM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 μM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.

We report herein, the design and synthesis of benzimidazole‐oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor‐2 (VEGFR‐2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF‐7, PANC‐1, hTERT‐HPNE and CCD‐19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR‐2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT‐HPNE and CCD‐19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR‐2 enzyme with half‐maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR‐2 (Protein Data Bank: 4ASD). [ABSTRACT FROM AUTHOR]

A method was proposed for the synthesis of some new molecular hybrids containing quinoline, 1,2,3-triazole and barbituric acid residues via Knoevenagel condensation, O-prorgylation and copper(I)-catalyzed azide alkyne cycloaddition reactions. The fourteen compounds were screened for the anticancer activity against MCF-7, MDA-MB-468 and MDA-MB-231 cell lines using MTT assay. Some compounds were screened for inhibitory activity against tyrosine kinase EGFR. Finally, in silico studies like molecular docking on EGFR and VEGFR-2 and ADMET have supported the in vitro results. [ABSTRACT FROM AUTHOR]

Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug‐loaded nanomicelle system comprising albendazole (ABZ) and paclitaxel (PTX), encapsulated in a novel carrier matrix of D‐tocopheryl polyethylene glycol 1000 succinate vitamin E (TPGS), soluplus and folic acid. Our objective was to develop and optimize this nanoparticulate delivery system using solvent evaporation techniques to enhance the therapeutic efficacy against ovarian cancer. The formulation process involved pre‐formulation, formulation, optimization, and comprehensive characterization of the micelles. Optimization was conducted through a 32 factorial design, focusing on the effects of polymer ratios on particle size, zeta potential, polydispersity index (PDI) and entrapment efficiency (%EE). The optimal formulation demonstrated improved dilution stability, as indicated by a critical micelle concentration (CMC) of 0.0015 mg/mL for the TPGS‐folic acid conjugate (TPGS‐FOL). Extensive characterization included differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and Fourier‐transform infrared spectroscopy (FTIR). The release profile exhibited an initial burst followed by sustained release over 90 h. The cytotoxic potential of the formulated micelles was superior to that of the drugs alone, as assessed by MTT assays on SKOV3 ovarian cell lines. Additionally, in vivo studies confirmed the presence of both drugs in plasma and tumour tissues, suggesting effective targeting and penetration. In conclusion, the developed TPGS‐Fol‐based nanomicelles for co‐delivering ABZ and PTX show promising results in overcoming drug resistance, enhancing solubility, sustaining drug release, and improving therapeutic outcomes in ovarian cancer treatment. [ABSTRACT FROM AUTHOR]

The coumarin nucleus is a simple privileged scaffold distributed in many plants. It has recently gained attention for its diverse biological activities and interactions with enzymes and receptors. The vascular endothelial growth factor receptor-2 (VEGFR-2), a receptor tyrosine kinase, is a crucial cancer target as it is involved in angiogenesis. This study employs virtual screening, molecular docking, and molecular simulation studies to identify potential coumarin candidates against VEGFR-2 from the COCONUT database. After thorough docking studies, CNP0056360, CNP0340213, and CNP0366287 were identified as final hits. Molecular dynamics simulation studies revealed strong stability and better binding energies for CNP0056360 and CNP0340213, outperforming lenvatinib; CNP0366287 showed comparable behaviour. The identified coumarins exhibited good in-silico pharmacokinetics and demonstrated low toxicity. [ABSTRACT FROM AUTHOR]

Plexiform lesions are a hallmark of pulmonary arterial hypertension (PAH) in humans and are proposed to stem from dysfunctional angioblasts. Broiler chickens (Gallus gallus) are highly susceptible to PAH, with plexiform-like lesions observed in newly hatched individuals. Here, we reported the emergence of plexiform-like lesions in the embryonic lungs of broiler chickens. Lung samples were collected from broiler chickens at embryonic day 20 (E20), hatch, and one-day-old, with PAH-resistant layer chickens as controls. Plexiform lesions consisting of CD133+/vascular endothelial growth factor receptor type-2 (VEGFR-2)+ angioblasts were exclusively observed in broiler embryos and sporadically in layer embryos. Distinct gene profiles of angiogenic factors were observed between the two strains, with impaired VEGF-A/VEGFR-2 signaling correlating with lesion development and reduced arteriogenesis. Pharmaceutical inhibition of VEGFR-2 resulted in enhanced lesion development in layer embryos. Moreover, broiler embryonic lungs displayed increased activation of HIF-1α and nuclear factor erythroid 2-related factor 2 (Nrf2), indicating a hypoxic state. Remarkably, we found a negative correlation between lung Nrf2 activation and VEGF-A and VEGFR-2 expression. In vitro studies indicated that Nrf2 overactivation restricted VEGF signaling in endothelial progenitor cells. The findings from broiler embryos suggest an association between plexiform lesion development and impaired VEGF system due to aberrant activation of Nrf2. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is among the main causes of mortality from cancer around the globe, affecting all genders. Current treatments mainly focus on tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, resistance mechanisms, such as the emergence of T790M and C797S EGFR mutations and upregulation of VEGFR-2, often hinder the effectiveness of TKIs. Thereby, EGFR and VEGFR-2 present an intriguing opportunity for the treatment of NSCLC by developing dual-acting drugs. This research aims to evaluate prospective Moringa oleifera L. (MO)-originated compounds to efficiently block both of these receptors. In our research, we screened a library of 200 compounds sourced from MO, a plant known for its remarkable therapeutic potential. We identified five intriguing phytocompounds: hesperetin, gossypetin, quercetin, gallocatechin, and epigallocatechin, as potential anti-cancer agents. The compounds have demonstrated notable binding affinity in virtual screening and multi-stage molecular docking analysis, surpassing the controls, Erlotinib and Bevacizumab + Rituximab. In addition, these compounds demonstrate top-notch drug-likeness and ADMET properties. The five promising drug candidates also had a strong ability to bind to receptors and stayed stable with them during the 200 ns molecular dynamics (MD) simulation and MM-GBSA calculation. Furthermore, DFT analysis indicates that hesperetin, gossypetin, and quercetagetin stand out as the most promising drug candidates among all others. The findings of our study suggest that these three therapeutic candidates can precisely target both EGFR and VEGFR-2 and can potentially act on both of these pathways as a single agent.

Abstract VEGFR-2 kinase inhibitors are clinically approved drugs that can effectively target cancer angiogenesis. However, such inhibitors have adverse effects such as skin toxicity, gastrointestinal reactions and hepatic impairment. In this study, machine learning and Topomer CoMFA, which is an alignment-dependent, descriptor-based method, were employed to build structural activity relationship models of potentially new VEGFR-2 inhibitors. The prediction ac-curacy of the training and test sets of the 2D-SAR model were 82.4 and 80.1%, respectively, with KNN. Topomer CoMFA approach was then used for 3D-QSAR modeling of VEGFR-2 inhibitors. The coefficient of q2 for cross-validation of the model 1 was greater than 0.5, suggesting that a stable drug activity-prediction model was obtained. Molecular docking was further performed to simulate the interactions between the five most promising compounds and VEGFR-2 target protein and the Total Scores were all greater than 6, indicating that they had a strong hydrogen bond interactions were present. This study successfully used machine learning to obtain five potentially novel VEGFR-2 inhibitors to increase our arsenal of drugs to combat cancer.

Abstract A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew’s correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.

Abstract Background Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. Results In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. Conclusions Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.

VEGFR-2 kinase inhibitors are clinically approved drugs that can effectively target cancer angiogenesis. However, such inhibitors have adverse effects such as skin toxicity, gastrointestinal reactions and hepatic impairment. In this study, machine learning and Topomer CoMFA, which is an alignment-dependent, descriptor-based method, were employed to build structural activity relationship models of potentially new VEGFR-2 inhibitors. The prediction ac-curacy of the training and test sets of the 2D-SAR model were 82.4 and 80.1%, respectively, with KNN. Topomer CoMFA approach was then used for 3D-QSAR modeling of VEGFR-2 inhibitors. The coefficient of q2 for cross-validation of the model 1 was greater than 0.5, suggesting that a stable drug activity-prediction model was obtained. Molecular docking was further performed to simulate the interactions between the five most promising compounds and VEGFR-2 target protein and the Total Scores were all greater than 6, indicating that they had a strong hydrogen bond interactions were present. This study successfully used machine learning to obtain five potentially novel VEGFR-2 inhibitors to increase our arsenal of drugs to combat cancer. [ABSTRACT FROM AUTHOR]

A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew's correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis. [ABSTRACT FROM AUTHOR]

To investigate the effect of Taohong Siwu decoction on the expression of vascular endothelial growth factor(VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), protein kinase B (Akt) gene and protein in brain microvascularendothelial cells (rBMECs) of rats with oxygen glucose deprivation (OGD) and its mechanism. The rBMECs were cultured andrandomly divided into normal group, model group, Taohong Siwu decoction (0.4 mg/m L ) group and Taohong Siwu decoction (0.8mg/mL) group. In addition to the normal group, the other three groups used oxygen glucose deprivation experiment to construct OGD injury model. Taohong Siwu decoction group was added with Taohong Siwu decoction at a concentration of 0.4 mg/mL and 0.8 mg/mL 1hbefore modeling, while the normal group and the model group were added with the same volume of normal saline. Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of VEGF, VEGFR-2 and Akt genes and proteins. Compared with the normal group, the apoptosis rate of the model group was significantly increased(P<0.05). Compared with the model group, the Taohong Siwu decoction (0.4 mg/mL) group and Taohong Siwu decoction (0.8 mg/mL) group decreased, and the Taohong Siwu decoction (0.8 mg/mL) group was the most significant(P<0.05). Compared with the normal group, the relative mRNAand protein expression levels of Akt, VEGFR-2 and VEGF in rBMECs of the model group were significantly increased (P<0.05). Com-pared with the model group, the Taohong Siwu decoction (0.4 mg/mL) group and Taohong Siwu decoction (0.8 mg/mL) group were significantly decreased, and the Taohong Siwu decoction (0.8 mg/mL) group was the most significant. Taohong Siwu decoction may inhibit the apoptosis of endothelial cells and maintain the integrity of endothelial cells by reducing the expression levels of VEGF, VEGFR-2 and Akt genes and proteins in rBMECs under OGD conditions, which may be one of the mechanisms of Taohong Siwu Decoction on brain protection. [ABSTRACT FROM AUTHOR]

The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer’s (AD) and Parkinson’s (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.

Background: Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. Results: In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. Conclusions: Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced. [ABSTRACT FROM AUTHOR]

Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a–5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a–5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein–ligand complexes. [ABSTRACT FROM AUTHOR]

The dual c-Met/vascular endothelial growth factor receptor 2 (VEGFR-2) TK inhibition is a good strategy to overcome therapeutic resistance to small molecules VEGFR-2 inhibitors. In this study, we designed 3-substituted quinazoline-2,4(1H,3H)-dione derivatives as dual c-Met/VEGFR-2 TK inhibitors. We introduced new synthetic methods for reported derivatives of 3-substituted quinazoline-2,4(1H,3H)-dione 2a–g, in addition to the preparation of some new derivatives namely, 3 and 4a–j. Three compounds namely, 2c, 4b, and 4e showed substantial amount of inhibition for both c-Met and VEGFR-2 TK (IC50 range 0.052–0.084 µM). Both compounds 4b, 4e showed HB with highly conserved residue Asp1222 in the HB region of c-Met TK. For VEGFR-2 TK, compound 4b showed HB with a highly conserved residue Asp1046 in the HB region. Compound 4e showed HB with Glu885 and Asp1046. Moreover, in silico prediction of pharmacokinetic and physicochemical parameters of target compounds was carried out using SwissADME website. The quinazoline-2,4(1H,3H)-dione derivatives are promising antiproliferative candidates that require further optimisation. New 3-substituted quinazoline-2,4(1H,3H)-dione derivatives were synthesised and characterised. Compounds 4b and 4e showed higher cytotoxic activity than cabozantinib against HCT-116 colorectal cell lines. Both compounds 4b and 4e showed less toxicity to WI38 normal cell line compared to HCT 116 colon cancer cell line. Compound 4b was superior to cabozantinib in VEGFR-2 inhibition while compound 2c was equipotent to cabozantinib. Compounds 4b and 4e showed remarkable c-Met inhibitory activity. Compounds 4b and 4e arrested cell cycle and induced significant levels of apoptosis. In silico ADME prediction revealed high oral bioavailability and enhanced water solubility of target compounds as compared to cabozantinib. Target compounds interacted with both c-Met and VEGFR-2 active site in similar way to cabozantinib. [ABSTRACT FROM AUTHOR]

Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds 5a and 6g were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 5a was especially good inhibitor for EGFR (IC50 = 0.086 µM) compared to Gefitinib (IC50 = 0.052 µM), moderate VEGFR-2 inhibitor (IC50 = 0.107 µM) compared to Sorafenib (IC50 = 0.0482 µM), and stronger Topo II inhibitor (IC50 = 2.52 µM) than Doxorubicin (IC50 = 3.62 µM). Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds. [ABSTRACT FROM AUTHOR]

To assess the effect of cabergoline on endometrial vascular endothelial growth factor receptor-2 (VEGFR-2) immunoexpression in an ovarian hyperstimulation syndrome (OHSS) rat model. Twenty-one immature female Wistar rats were assigned into three groups: group 1, the control group; group 2, stimulated with gonadotropins to mimic OHSS; and group 3, in which an OHSS protocol was induced and thereafter treated with cabergoline (100 μg/kg/day). Body weight, ovarian volume, corpora lutea numbers, and endometrial VEGFR-2 expression were compared between the groups. Weight gain and ovarian volume were highest in the OHSS-placebo group, while cabergoline administration significantly reversed those effects (p = 0.001 and p = 0.001, respectively). VEGFR-2 stained cells were significantly lower in groups 2 and 3 compared to group 1 (p = 0.002). Although VEGFR-2 expression was lowest in group 3, the difference was not statistically significant. Corpora lutea numbers were also similar (p = 0.465). While successful implantation requires a vascularized receptive endometrium, impaired expression of VEGFR-2 and disrupted endometrial angiogenesis due to cabergoline administration may be associated with IVF failure in fresh OHSS cycles. The insignificant decrease in endometrial VEGFR-2 expression observed in this research needs to be investigated by further studies involving additional techniques such as immunoblotting and/or RT-PCR analyses. [ABSTRACT FROM AUTHOR]

Standard imaging cannot reliably predict the nature of renal tumors. Among malignant renal tumors, clear cell renal cell carcinoma (ccRCC) is the most common histological subtype, in which the vascular endothelial growth factor 2 (VEGFR-2) is highly expressed in the vascular endothelium. BR55, a contrast agent for ultrasound imaging, consists of gas-core lipid microbubbles that specifically target and bind to the extracellular portion of the VEGFR-2. The specific information provided by ultrasound molecular imaging (USMI) using BR55 was compared with the vascular tumor expression of the VEGFR-2 by immunohistochemical (IHC) staining in a preclinical model of ccRCC. Patients' ccRCCs were orthotopically grafted onto Nod-Scid-Gamma (NSG) mice to generate patient-derived xenografts (PdX). Mice were divided into four groups to receive either vehicle or axitinib an amount of 2, 7.5 or 15 mg/kg twice daily. Perfusion parameters and the BR55 ultrasound contrast signal on PdX renal tumors were analyzed at D0, D1, D3, D7 and D11, and compared with IHC staining for the VEGFR-2 and CD34. Significant Pearson correlation coefficients were observed between the area under the curve (AUC) and the CD34 (0.84, p < 10−4), and between the VEGFR-2-specific signal obtained by USMI and IHC (0.72, p < 10−4). USMI with BR55 could provide instant, quantitative information on tumor VEGFR-2 expression to characterize renal masses non-invasively. [ABSTRACT FROM AUTHOR]

VEGFR-2 is required for tumor angiogenesis and metastasis. As a cancer therapeutic strategy, blocking VEGFR-2 signaling pathway has gained much interest. Our work aimed to design and synthesize two series of new tolfenamic acid (TA) derivatives containing hydrazine-1-carbothioamide (compounds 4A-E) or 1,3,4-oxadiazole (compounds 5A-E) as possible VEGFR-2 tyrosine kinase inhibitors. The designed compounds were successfully synthesized using conventional organic chemical methods. Docking studies were performed to learn how the newly synthesized compounds bind to VEGFR-2 tyrosine kinase. The new compounds were evaluated in vitro for their cytotoxic activity against three human cancer cell lines. Cell cycle progression and induction of apoptosis by flow cytometry and immunoblotting were investigated. Molecular modeling showed that compounds 4A, 4B, 4C, 5A, and 5B have high docking score (ΔG) in the active pocket of the molecular target VEGFR-2. The new TA derivatives also showed good pharmacokinetic characteristics. Compound 4B, the most potent cytotoxic TA derivative, was found to have an EC50 value comparable to that of sorafenib against VEGFR-2, causing cell cycle arrest at the G2/M phase and induction of the extrinsic and endoplasmic reticulum apoptosis pathways. In summary, compound 4B has the potential to be an antagonist of VEGFR-2, which is overexpressed in solid tumors. [ABSTRACT FROM AUTHOR]

A series of the 2-nitrochalcones 3a–3k was synthesized and evaluated for cytotoxicity against the human lung adenocarcinoma (A549) and human embryonic kidney (HEK293-T) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The 3-(4-fluorophenyl) 3c and the 3-(4-(1,1,2,2-tetrafluoroethoxy)phenyl derivative 3k induced early (25–29%) and late (48–60%) apoptosis of A549 cells as determined by the Annexin V-FITC/PI method. The 3-(4-fluorophenyl) 3c, 3-(4-methoxyphenyl) 3h, 3-(2,3,4-trimethoxyphenyl) 3j and the 3-(4-(1,1,2,2-tetrafluoroethoxy)phenyl derivative 3k were also found to exhibit significant inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase compared to staurosporine (0.035 ± 0.002 µM) or nintedanib (IC50 = 0.021 ± 0.001 µM) with IC50 values of 31.49 ± 0.02, 39.95 ± 0.17, 36.90 ± 0.16 and 29.10 ± 0.16 µM, respectively. Molecular docking studies were also conducted on 3c and 3k as representative models to recognize the hypothetical binding motif of the title compounds within the active site of VEGFR-2. [ABSTRACT FROM AUTHOR]

Thiazole and its derivatives have received a lot of attention from researchers due to its wide biological, pharmacological, and anticancer properties. A novel series of 2-[2-[4-Hydroxy-3-substituted benzylidene hydrazinyl]-thiazole-4[5H]-ones (4a–c) and acetoxy derivative (5) were synthesized via using thiosemicarbazones (2a–c). The structure of the thiazole derivatives (4a–c) and 5 in these compounds was confirmed by spectroscopic techniques (IR and NMR), as well as elemental investigations. The synthesized derivatives biological activity was assessed based on their capacity to suppress the growth of the cancer cell lines MCF-7 and HepG2, as well as to halt the cell cycle and trigger apoptosis. Among the synthesized thiazole derivatives, compound 4c was found the most active derivative, with inhibitory concentrations IC50 = 2.57 ± 0.16 and 7.26 ± 0.44 µM in MCF-7 and HepG2, respectively, compared to Staurosporine as the standard drug with IC50 6.77 ± 0.41 and 8.4 ± 0.51 µM, respectively. Additionally, compound 4c blocked vesicular endothelial growth factor receptor-2 (VEGFR-2), according to our results (IC50 = 0.15 µM), compared to Sorafenib (IC50 = 0.059 µM) as the standard drug. Moreover, compound 4c induced cell cycle arrest at the G1/S phase, increasing the percentage and accumulation of cancer cells (DNA content) in the pre-G1 phase by 37.36% in MCF-7 cancer cells compared to untreated MCF-7 cells at 2.02%. Also, compound 4c increased the percentage of early and late apoptosis from 0.51% and 0.29%, respectively, in the case of the MCF-7 untreated control sample to 22.39% and 9.51%, respectively, in the MCF-7 treated sample. Furthermore, molecular docking studies of compounds 4a–c and 5 were conducted with four key proteins (aromatase, epidermal growth factor receptor (EGFR), cyclin-dependent kinase 2 (CDK2), and B-cell lymphoma 2 (Bcl-2)) that stimulate the growth, proliferation, and development of cancer cells. Compound 4c exhibited good docking scores with a promising and potential binding affinity toward the active site of selected docked proteins. According to these results, compound 4c showed efficient cytotoxic activity against the tested cancer cells. [ABSTRACT FROM AUTHOR]

Haemangiomas (HAs) are prevalent vascular endothelial cell tumours. With respect to the possible involvement of HIF‐1α in HAs, we have explored its role in haemangioma endothelial cell (HemEC) proliferation and apoptosis. shRNA HIF‐1α and pcDNA3.1 HIF‐α were manipulated into HemECs. HIF‐α, VEGF, and VEGFR‐2 mRNA and protein levels were assessed by qRT‐PCR and Western blotting. Cell proliferation and viability, cell cycle and apoptosis, migration and invasion, and ability to form tubular structures were assessed by colony formation assay, CCK‐8, flow cytometry, Transwell assay, and tube formation assay. Cell cycle‐related protein levels, and VEGF and VEGFR‐2 protein interaction were detected by Western blot and immunoprecipitation assays. An Haemangioma nude mouse model was established by subcutaneous injection of HemECs. Ki67 expression was determined by immunohistochemical staining. HIF‐1α silencing suppressed HemEC neoplastic behaviour and promoted apoptosis. HIF‐1α facilitated VEGF/VEGFR‐2 expression and the VEGF had interacted with VEGFR‐2 at protein ‐ protein level. HIF‐1α silencing arrested HemECs at G0/G1 phase, diminished Cyclin D1 protein level, and elevated p53 protein level. VEGF overexpression partially abrogated the effects of HIF‐1α knockdown on inhibiting HemEC malignant behaviours. Inhibiting HIF‐1α in nude mice with HAs repressed tumour growth and Ki67‐positive cells. Briefly, HIF‐1α regulated HemEC cell cycle through VEGF/VEGFR‐2, thus promoting cell proliferation and inhibiting apoptosis. [ABSTRACT FROM AUTHOR]