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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

A computer‐assisted drug design (CADD) approach was utilized to design a new acetamido‐N‐(para‐fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T‐1‐APFPB), following the pharmacophoric features of VEGFR‐2 inhibitors. The stability and reactivity of T‐1‐AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T‐1‐AFPB's potential to bind with and inhibit VEGFR‐2. The precise binding of T‐1‐AFPB against VEGFR‐2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM‐GBSA, and PCA studies. Then, T‐1‐AFPB (4‐(2‐(3,7‐Dimethyl‐2,6‐dioxo‐2,3,6,7‐tetrahydro‐1H‐purin‐1‐yl)acetamido)‐N‐(4‐fluorophenyl)benzamide) was semi‐synthesized and the in vitro assays showed its potential to inhibit VEGFR‐2 with an IC50 value of 69 nM (sorafenib's IC50 was 56 nM) and to inhibit the growth of HepG2 and MCF‐7 cancer cell lines with IC50 values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T‐1‐AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T‐1‐AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T‐1‐APFPB providing it as a promising lead VEGFR‐2 inhibitor for further development aiming at cancer therapy. [ABSTRACT FROM AUTHOR]

Metastasis, the dissemination of tumor cells, stands as the second most prominent contributor to mortality arising from breast cancer. To counteract this phenomenon, the molecular markers associated with angiogenesis, particularly vascular endothelial growth factor (VEGF) and its receptor (VEGFR), have emerged as promising strategies for impeding the progression of tumor cells. Compounds like pyrimidines, coumarins, oxadiazoles, and triazoles have undergone comprehensive investigations due to their notable anticancer potential, highlighting their encouraging capacities in inhibiting VEGFR-2, an essential mediator of angiogenesis signaling. Herein, we have synthesized pyrimidine–triazoles and oxadiazole–triazoles using electrochemical and conventional methods. The newly synthesized compounds were evaluated for anticancer activity against MCF-7 breast cancer cells, and it was found that the compounds 8a and 8b showed IC50 values of 5.29 and 15.54 μM, respectively. Our in silico mode of action revealed that these compounds could target VEGFR-2, which was further evidenced by our in silico structure-based bioinformatic analysis. In conclusion, we reported an electrochemical method to prepare novel drug-like compounds, based on triazole and other heterocyclic hybrids, that could be used to design VGFR-targeting drugs. [ABSTRACT FROM AUTHOR]

A series of 1,3‐disubstituted‐2‐thioxoimidazolidin‐4‐one and diazine derivatives were synthesized and confirmed through IR, NMR, and mass spectrometry. The in vitro cytotoxic activity of synthesized compounds against HePG2 and MCF‐7 cells were assessed by MTT assay. Furthermore, Aromatase, VEGFR‐2, B‐Raf, cell cycle, Annexin V, caspase‐3 and sulphatase expression by PCR, and β‐catenin expression by western blot were estimated. The results revealed that the synthesized compounds possess cytotoxic activity against HePG2 and MCF‐7 cell lines. Compound 11 (2,2′‐(1E,1′E)‐1,1′‐(hydrazine‐1,2‐diylidene) bis (ethan‐1‐yl‐1‐ylidene) bis (4‐(phenyldiazenyl) phenol) had greater cytotoxic activity than staurosporine (6.24 μg/mL), with IC50 of 2.55 μg/mL against HepG2 cells and (4.21 μg/mL) against MCF‐7 cells. Moreover, the inhibitory activity against aromatase was (0.156 μg/mL), (0.23 μg/mL) against VEGFR2, and (0.25 μg/mL) against B‐Raf. Also, this compound decreased DNA content of HepG2 cells in the S phase and the G2/M phase, and increased the apoptosis in Annexin measurement. By real‐time PCR, This compound up‐regulated the expression of caspase‐3 in HepG2 cells, reduced the expression of sulphatase gene in HepG2 cells, and reduced β‐catenin expression in HepG2 by western blot analysis. Consequently, the synthesized derivatives could be a promising scaffold for the development of potent anti‐cancer agents due to their apoptotic and anti‐inflammatory activities. [ABSTRACT FROM AUTHOR]

New Zn(II), Cd(II), VO(IV), and UO2(VI) solvatochromic complexes derived from 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde‐semicarbazone ligand (H2L) were synthesized and established by elemental analyses, spectral (IR, UV, NMR, mass spectra), molar conductivity measurements, magnetic susceptibility, and thermal gravimetric analysis (TGA). The ligand coordinates with metal ions through ONO chelating sites, forming an octahedral geometry arrangement, except UO2(VI) that showed pentagonal bipyramidal geometry. Using Coats–Redfern methodology, the kinetic parameters (Ea, A, ΔH, ΔS, and ΔG) of the thermal decomposition steps were calculated and discussed. The complexes showed solvatochromic behavior that used to estimate the ground and excited state dipole moments. Optimization and structural parameters were carried out by density function theory (DFT) at B3LYP/GENECP method at 6‐311G(d,p) basis set for C, H, N, and O atoms and SDD (Stuttgart/Dresden) basis set for the metal atoms and interrelated with the experimental results. The complexes were tested for antimicrobial efficiency against Gram‐positive bacteria, Gram‐negative bacteria, yeast, and fungi. Also, antitumor activity was investigated against HepG‐2 cell line. Finally, the new synthesized complexes upon subjecting to molecular docking and distinguishable results showed outstanding inhibition results of VEGFR‐2 via achieving a high stabilization level inside the largest pocket of 1YWN protein. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factors (VEGFs) are specific cytokines involved in angiogenesis and do so via binding to vascular endothelial growth factor receptors (VEGFRs), a type of receptor tyrosine kinase. VEGFs are reported to facilitate angiogenesis in physiological (embryogenesis) and pathological (tumor) conditions. The overexpression of VEGFs and consequently VEGFRs is reported in tumorigenic conditions. Several VEGFR inhibitors currently used as anticancer drugs to prevent angiogenesis are sunitinib, sorafenib, etc. To identify new potential candidates as VEGFR inhibitors, a classification study using a large and diverse dataset of VEGFR inhibitors from the BindingDB database has been conducted. The KNIME platform was used to calculate molecular and fingerprint‐based descriptors and several classification algorithms viz. linear regression (LR), k‐nearest neighbor (kNN), decision tree (DT), random forest (RF), and gradient boosted tree (GBT) were employed to build the classification model. The model performance was evaluated by accuracy, precision, recall, and F1 score of the test set. The best LR, kNN, DT, RF, and GBT classifiers had the F1 score of 0.81, 0.87, 0.82, 0.87, and 0.87, respectively. The assorted 5120 VEGFR inhibitors were clustered into 10 subsets, and the structural features of each subset were assessed along with the identification of significant fragments in active and inactive compounds. The automated classifier model developed using the KNIME platform could serve as an important platform for screening and designing molecules as VEGFR inhibitors. [ABSTRACT FROM AUTHOR]

Background: The vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in melanoma development and progression. Peptide vaccines have shown great potential in cancer immunotherapy by targeting VEGFR-2 as a tumor-associated antigen and boosting the immune response against both tumor cells and tumor endothelial cells. Despite this, the low efficiency of peptide vaccines has resulted in moderate therapeutic results in the majority of studies. Enhancing the delivery of peptide vaccines using nanoliposomes is an important strategy for improving the efficacy of peptide vaccines. In this regard, we designed VEGFR-2-derived peptides restricted to both mouse MHC I and human HLA-A*02:01 using immunoinformatic tools and selected three peptides representing the highest binding affinities. The peptides were encapsulated in nanoliposomal formulations using the film method plus bath sonication and characterized for their colloidal properties. Results: The mean diameter of peptide-encapsulated liposomes was around 135 nm, zeta potential of − 17 mV, and encapsulation efficiency of approximately 70%. Then, vaccine formulations were injected subcutaneously in mice bearing B16F10-established melanoma tumors and their efficiency in triggering immunological, and anti-tumor responses was evaluated. Our results represented that one of our designed VEGFR-2 peptide nanoliposomal formulations (Lip-V1) substantially activated CD4+ (p < 0.0001) and CD8+ (P < 0.001) T cell responses and significantly boosted the production of IFN-γ (P < 0.0001) and IL-4 (P < 0.0001). Furthermore, this formulation led to a significant decrease in tumor volume (P < 0.0001) and enhanced survival (P < 0.05) in mice. Conclusion: Our findings suggest that the nanoliposomal formulation containing VEGFR-2 peptides could be a promising therapeutic vaccination approach capable of eliciting strong antigen-specific immunologic and anti-tumor responses. [ABSTRACT FROM AUTHOR]

This work focuses on the development of thirteen benzylethylenearyl ureas and one carbamate. After the synthesis and purification of the compounds, we studied their antiproliferative action on cell lines, such as HEK-293, and cancer ones, such as HT-29, MCF-7 or A-549, on the immune Jurkat T-cells and endothelial cells HMEC-1. Compounds C.1, C.3, C.12 and C.14 were selected for further biological studies to establish their potential as immunomodulating agents. Some of the derivatives exhibited significant inhibitory effects on both targets: PD-L1 and VEGFR-2 in the HT-29 cell line, showing that urea C.12 is active against both targets. Some compounds could inhibit more than 50% of cancer cell proliferation compared to non-treated ones when assessed in co-cultures using HT-29 and THP-1 cells. In addition, they significantly reduced CD11b expression, which is a promising target for immune modulation in anticancer immunotherapies. [ABSTRACT FROM AUTHOR]

The high vascularization of glioma highlights the potential value of anti-angiogenic therapeutics for glioma treatment. Previously, we designed a novel vascular-targeting and blood–brain barrier (BBB)-penetrating peptide, TAT-AT7, by attaching the cell-penetrating peptide TAT to a vascular-targeting peptide AT7, and we demonstrated that TAT-AT7 could target binding to the vascular endothelial growth factor receptor 2 (VEGFR-2) and Neuropilin-1 (NRP-1), which are both highly expressed in endothelial cells. TAT-AT7 has been proven to be a good targeting peptide which could effectively deliver the secretory endostatin gene to treat glioma via the TAT-AT7-modified polyethyleneimine (PEI) nanocomplex. In the current study, we further explored the molecular binding mechanisms of TAT-AT7 to VEGFR-2 and NRP-1 and its anti-glioma effects. Accordingly, TAT-AT7 was proven to competitively bind to VEGFR-2 and NRP-1 and prevent VEGF-A165 binding to the receptors by the surface plasmon resonance (SPR) assay. TAT-AT7 inhibited endothelial cells' proliferation, migration, invasion, and tubule formation, as well as promoted endothelial cells' apoptosis in vitro. Further research revealed that TAT-AT7 inhibited the phosphorylation of VEGFR-2 and its downstream PLC-γ, ERK1/2, SRC, AKT, and FAK kinases. Additionally, TAT-AT7 significantly inhibited angiogenesis of zebrafish embryo. Moreover, TAT-AT7 had a better penetrating ability and could penetrate the BBB into glioma tissue and target glioma neovascularization in an orthotopic U87-glioma-bearing nude mice model, and exhibited the effect of inhibiting glioma growth and angiogenesis. Taken together, the binding and function mechanisms of TAT-AT7 were firstly revealed, and TAT-AT7 was proven to be an effective and promising peptide for the development of anti-angiogenic drugs for targeted treatment of glioma. [ABSTRACT FROM AUTHOR]

Thirteen benzylethoxyaryl ureas have been synthesized and biologically evaluated as multitarget inhibitors of VEGFR-2 and PD-L1 proteins to overcome resistance phenomena offered by cancer. The antiproliferative activity of these molecules on several tumor cell lines (HT-29 and A549), on the endothelial cell line HMEC-1, on immune cells (Jurkat T) and on the non-tumor cell line HEK-293 has been determined. Selective indexes (SI) have been also determined and compounds bearing p-substituted phenyl urea unit together with a diaryl carbamate exhibited high SI values. Further studies on these selected compounds to determine their potential as small molecule immune potentiators (SMIPs) and as antitumor agents have been performed. From these studies, we have concluded that the designed ureas have good tumor antiangiogenic properties, exhibit good inhibition of CD11b expression, and regulate pathways involved in CD8 T-cell activity. These properties suggest that these compounds could be potentially useful in the development of new cancer immune treatments. [ABSTRACT FROM AUTHOR]

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor‐2 (VEGFR‐2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR‐2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51‐fold increment in total apoptotic level in leukemia cell line HL‐60(TB) and a 6.91‐fold increase in the caspase‐3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram‐positive and Gram‐negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 μg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram‐negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR‐2 active site and compounds 3a–c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties. [ABSTRACT FROM AUTHOR]

Acetylsalicylic acid (ASA) is a well-established drug for heart attack and stroke prophylaxis. Furthermore, numerous studies have reported an anti-carcinogenic effect, but its exact mechanism is still unknown. Here, we applied VEGFR-2-targeted molecular ultrasound to explore a potential inhibitory effect of ASA on tumor angiogenesis in vivo. Daily ASA or placebo therapy was performed in a 4T1 tumor mouse model. During therapy, ultrasound scans were performed using nonspecific microbubbles (CEUS) to determine the relative intratumoral blood volume (rBV) and VEGFR-2-targeted microbubbles to assess angiogenesis. Finally, vessel density and VEGFR-2 expression were assessed histologically. CEUS indicated a decreasing rBV in both groups over time. VEGFR-2 expression increased in both groups up to Day 7. Towards Day 11, the binding of VEGFR-2-specific microbubbles further increased in controls, but significantly (p = 0.0015) decreased under ASA therapy (2.24 ± 0.46 au vs. 0.54 ± 0.55 au). Immunofluorescence showed a tendency towards lower vessel density under ASA and confirmed the result of molecular ultrasound. Molecular US demonstrated an inhibitory effect of ASA on VEGFR-2 expression accompanied by a tendency towards lower vessel density. Thus, this study suggests the inhibition of angiogenesis via VEGFR-2 downregulation as one of the anti-tumor effects of ASA. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel triazole derivatives were designed and synthesized as VEGFR-2/telomerase inhibitors. • 7b showed the best average GI% (75.69 %) surpassing the average GI% of Dox (65.79 %). • 5d displayed the lowest IC 50 values at HNO-97 and FaDu. • 5a prompted telomerase downregulation by 0.60-fold, and 5b induced VEGFR-2 downregulation by 0.42-fold changes. • 5a upregulated caspases 3, 8, and 9, and downregulated CDK-2, 4, and 6. In this current work, we dedicated efforts to designing and synthesizing new 1,2,3-triazole-analogues (5a-d), (6a-d), and (7a-c) to act as dual VEGFR-2 and telomerase inhibitors with promising apoptotic potential. The synthesized analogues were examined against eleven diverse types of cancer cells and two normal cells to assess their ability to inhibit cell growth (GI%). Obviously, compound 7b showed the best average GI% (75.69 %) surpassing the average GI% of Dox (65.79 %). Compound 5d showed the lowest IC 50 values (25.86 and 51.91 µM) against HNO-97 and FaDu cancer cells, respectively. Besides, compound 5a exhibited the lowest IC 50 value (15.46 µM) against HCT 116 , whereas compound 6b revealed the lowest IC 50 value (31.14 µM) against HuH7. Besides, candidates 5a , 5b , 5d , and 7a showed prominent inhibitory results towards VEGFR-2 protein with decreasing its expression by 0.33, 0.42, 0.38 and 0.26-fold change, respectively. However, compounds 5a , 5b , 5d , and 7a showed promising inhibitory results towards telomerase protein and decreased its expression by 0.60, 0.50, 0.52, and 0.44-fold change, respectively. Additionally, it was clear that compound 5a was able to upregulate the expression of Caspases 3, 8, and 9 proteins by 2.19, 1.83, and 1.62-fold change, respectively. Besides, 5a was able to downregulate the expression of CDK-2, CDK-4, and CDK-6 proteins by 0.50, 0.43, and 0.13-fold change, respectively. Obviously, compound 5a halted the cell cycle at the G1, S, and G2-M phases in HCT 116 cells. Subsequently, the synthesized 1,2,3-triazole analogues can be treated as lead VEGFR-2 and telomerase inhibitors with potential apoptotic activity for future optimization and cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • 3-indolyl substituted phenyl pyrazolo-carboxamide hybrids were synthesized. • IC 50 value of 2.12 ± 0.19 μM was obtained for 7b against MCF-7 cancer cell line. • Compound 7b also exhibited VEGFR-2 inhibition with an IC 50 value of 2.83 ± 0.86 μM. • 7b was able to induce apoptosis and generate superoxide ROS. The progression of tumors is intricately linked to angiogenesis, the formation of new blood vessels, driven primarily by the release of growth factors such as Vascular Endothelial Growth Factor (VEGF). Targeting VEGF signaling through its receptor kinase (VEGFR-2) has emerged as a promising anti-angiogenic strategy for cancer therapy. In this study, we designed and synthesized a series of novel chemical entities based on 3-indolyl substituted phenyl pyrazole-carboxamides through docking studies upon considering the structure of sorafenib and its pattern of type II inhibition of VEGFR-2. Among the synthesized hybrids, 7b was able to significantly inhibit the growth of cancer cell lines, specifically against MCF-7 at 2.12 ± 0.19 μM. Compound 7b also efficiently inhibited VEGFR-2 kinase at a concentration of 2.83 ± 0.86 μM during the in vitro studies. Mechanistic studies revealed that 7b induced apoptosis evidenced by AO/EB, DAPI, and DCFDA staining, and its impact on the migratory ability of the cancer cells were also studied. These findings highlight the potential of 7b as a lead candidate for further development of anti-angiogenic therapies targeting VEGFR-2. [ABSTRACT FROM AUTHOR]

• A new series of vatalanib analogs based on quinoxaline has been designed, synthesized, and biologically evaluated as anticancer candidates. • Cytotoxic activities were evaluated against HepG2 and HCT116 cell lines. • In vitro VEGFR-2 inhibitory activity, cell cycle and apoptosis rate were evaluated for the most promising candidate. • Molecular docking and in silico ADMET study studies were carried out for the synthesized compounds. In our attempts to improve pharmacokinetics and pharmacodynamics characters of vatalanib, four strategies of the drug design were applied to design and synthesis new quinoxaline based vatalanib analogs. Antiproliferative activities of the synthesized compounds were investigated against two tumor cell lines (HepG2 and HCT‐116) using vatalanib as a positive control. The new candidates showed promising anticancer activity against two tested cancer cell lines with IC 50 values ranging from 6.04 ± 0.19 to 100.15 ± 3.26 µM, in particular compounds 11b and 11c which were more potent than vatalanib. The most potent was the 4-benzoylquinoxaline derivative 11b (IC 50 = 6.04 ± 0.19 µM and 15.58 ± 0.58 µM) compared to vatalanib (IC 50 of 25.27 ± 0.84 µM and 43.91 ± 1.64 µM) against HepG2 and HCT116, respectively. The selectivity indices of 11b were found to be approximately 14 and 5 towards HepG2 and HCT116, respectively. While vatalanib showed selectivity indices of about 5 and 3 towards HepG2 and HCT116, respectively. The most promising compound 11b was further investigated in HepG‐2 cells for its apoptotic effect, cell cycle arrest and in vitro VEGFR-2 inhibitory activity as the main mechanisms of cell death. It was found that 11b can induce apoptosis and arrest the cell cycle at the at G1 phase in addition to, compound 11b showed effective inhibition of VEGFR-2 with IC 50 of 0.918 ± 0.033 µM compared to vatalanib (IC 50 of 0.265 ± 0.009 µM). Deep computational studies were created for the designed compounds including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions to evaluate the prospective drug candidates. The results of the docking study were consistent with biological testing, furthermore, in silico ADMET study revealed the superior pharmacokinetics characters of the new candidates over vatalanib. So, the current work suggests that the 4-benzoylquinoxaline-1-yl-acetamide derivatives, especially 11b, can serve as lead molecules for development of new effective anticancer drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

New thiadiazolopyrimidine-ornamented pyrazolones (4a – 8b) have been synthesized by a cyclocondensation reaction of 3a , b with different active methylene compounds. The structure of our products was confirmed via different physical and spectroscopic data. We assessed all newly thiadiazolopyrimidine-ornamented pyrazolones' potential to inhibit angiogenesis, metastasis, and cancer growth by utilizing in-silico investigations focused on the VEGFR-2 signaling pathway and elucidate their pharmacokinetic features using ADMET. Based on our results, compound 8b was chosen for in vitro evaluation since it had the highest binding energy of −10.252 kcal/mol using molecular docking. Compound 8b significantly damaged the T47D (IC 50 = 33.01 ± 2.2 μM) cells, without any toxic effect on normal cells in comparison to chemotheraputic FDA approved drug cisplatin (Cis) (IC 50 = 3.163 ± 1.7 μM). Additionally, compound 8b significantly suppressed the VEGFR-2 receptor protein that triggers the inhibition of PI3K/Akt genes which causes mitochondrial membrane malfunction resulting in Bax overexpression and Bcl-2 downregulation levels. Besides, compound 8b showed a notable decrease in the levels of nitric oxide (NO) production levels and arrested the cell cycle in the G0/G1 stage. These outcomes demonstrated that compound 8b adhered to Lipinski's rules and may serve as a potential candidate for future breast cancer treatments via obstructing the VEGFR-2/PI3K/Akt signaling pathway, which in turn prevents metastasis, angiogenesis, and proliferation. Systematic overview for compound 8b that may serve as a potential candidate for breast cancer treatments via obstructing the VEGFR2/PI3K/Akt signaling pathway. [Display omitted] [ABSTRACT FROM AUTHOR]

The global prevalence of oral squamous cell carcinoma (OSCC) has been increasing. OSCC at the advanced stage tends to resist conventional treatment and causes local recurrence and distant metastasis, resulting in poor prognosis. Therefore, detecting this cancer at an early stage and performing early intervention are important. Promising biomarkers to detect OSCC have yet to be established; however, microRNAs (miRNAs/miRs) serve a crucial role in OSCC tumorigenesis and may be potential biomarkers. In the present case report, the availability of salivary miRNAs as a therapeutic and prognostic marker for patients with OSCC was assessed. The patient was a 33-year-old woman who was diagnosed with advanced OSCC of the tongue, and their miRNA profile isolated from a saliva sample at each clinical course was evaluated. Microarray analysis of the salivary samples revealed changes in the levels of four miRNAs (hsa-miR-6798-5p, miR-6803-5p, miR-6805-5p and miR-6845-5p) in accordance with the clinical course. Neoadjuvant chemotherapy and surgical procedure decreased the levels, whereas the levels increased when the patient was diagnosed with lung metastasis. Furthermore, tongue and lung metastatic lesion specimens exhibited expression of the vascular endothelial growth factor receptor-2, which is regulated by the four miRNAs. Accordingly, the present report proposed that salivary miRNAs could be a therapeutic and prognostic biomarker for OSCC. [ABSTRACT FROM AUTHOR]

Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the expression of several differentiation markers in the apical papilla (AP) and dental pulp (DP) of human permanent teeth. Twenty young human teeth were extracted and classified according to three Moorrees tooth development stages: initial root formation (Ri), root length ½ (R1/2), and root length complete (Rc). Immunohistochemical assays were performed using STRO-1, VEGF Receptor-2, Neurofilament heavy (NFH), and Nestin antibodies and analyzed under light microscopy. Decalcified, formalin fixed paraffin embedded tooth sections stained with hematoxylin and eosin showed an apical cell rich zone between the DP and AP. The AP revealed fewer vascular and cellular components than the DP. STRO-1 was expressed on vascular and neuronal elements beneath the odontoblast (OB) and in the sub-odontoblastic (SOB) zone, and VEGFR-2 positive cells were observed in the endothelium, arterioles, and blood vessels. Neuroepithelial stem cell protein (Nestin) was highly expressed in differentiated odontoblasts in the predentin odontotoblast and odontoblast cell processes. Neurofilament heavy (NFH) was expressed in mature axons throughout the DP. STRO-1 and VEGFR-2 microvascular expression was higher at the stages Ri and R1/2 while STRO-1 and NFH expression showed strong spatial distribution of Rc neuronal elements as compared to Ri and R1/2. Differentiated OB and SOB cells showed Nestin expression, indicating a reservoir of newly differentiated odontoblast-like cells. [ABSTRACT FROM AUTHOR]

Purpose: Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. Methods: Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. Results: Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. Conclusions: This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects. [ABSTRACT FROM AUTHOR]

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a–e, 10a–c and 12a–c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (−9.900 and −9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 μM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 μM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Background and objectives: Nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB) inhibition results in an increase in apoptosis. It has been demonstrated that NF-κB subunit p65 phosphorylation at the IκB kinase phosphorylation site serine 536 (Ser536) is essential for the NF-κB nuclear translocation and activation. Therefore, NF-κB can be downregulated by suppressing its phosphorylation. The vascular endothelial growth factor receptor-2 (VEGFR-2) suppression could result in apoptosis induction. Therefore, targeting these pathways via VEGFR-2 inhibitors might have therapeutic potential for cancer treatment. It has been indicated that an antagonist peptide of VEGF, referred to as VGB3, could neutralize and recognize VEGFR2 in the tumoral and endothelial cells. This study aimed to induce apoptosis in human umbilical vein endothelial cells (HUVEC) cells through the inhibition of these signaling pathways. Methods: Effects of different concentrations of VGB3 (1-200 ng/ml) were evaluated on the viability of HUVEC cells using MTT assay. In addition, downstream signaling pathways in HUVE cells were evaluated through quantitative assessment of protein expression via western blotting. Results: The results demonstrated that VGB3 treatment inhibited the growth of HUVEC cells. Moreover, Bcl-2 was decreased in the cells treated with the VGB3 compared to the control. Furthermore, VGB3 significantly enhanced the cleavedcaspase7 levels, which is an indicator of apoptosis progression. Altogether, VGB3 enhanced apoptosis in HUVEC cells. Conclusion: Our results indicate that the peptide might be a potential candidate for antitumor therapy via inhibiting the NF-κB pathway. [ABSTRACT FROM AUTHOR]

Resent study suggests that c-kit+ cells in bone marrow-derived MSCs may differentiate toward cardiamyocytes. However, the properties of c-kit+ MSCs remain unclear. This study isolated c-kit+VEGFR-2+ cells from rat bone marrow-derived MSCs, and assessed potential of c-kit+VEGFR-2+ MSCs to differentiate towards cardiovascular cells and their efficiency of repairing the infarcted myocardium after transplantation. Gene expression profile of the cells was analyzed with RNA-sequencing. Potential of differentiation of the cells was determined after induction. Rat models of myocardial infarction were established by ligation of the left anterior descending coronary artery. The cells were treated with hypoxia and serum deprivation for four hours before transplantation. Improvement of cardiac function and repair of the infarcted myocardium were assessed at four weeks after transplantation. Gene expression profile revealed that c-kit+VEGFR-2+ MSCs expressed most smooth muscle-specific and myocardium-specific genes, while expression of endothelium-specific genes was upregulated significantly. After induction with VEGF or TGF-β for two weeks, the cells expressed CD31 and α-SMA respectively. At three weeks, BMP-2-induced cells expressed cTnT. After transplantation of the cells, cardiac function was improved, scar size of the infarcted myocardium was decreased, and angiogenesis and myocardial regeneration were enhanced significantly. Moreover, paracrine in the myocardium was increased after transplantation. These results suggest that c-kit+VEGFR-2+ MSCs have a potential of differentiation towards cardiovascular cells. Transplantation of c-kit+VEGFR-2+ MSCs is effective for repair of the infarcted myocardium. c-kit+VEGFR-2+ MSCs may be a reliable source for cell therapy of ischaemic diseases. [ABSTRACT FROM AUTHOR]

Background: Inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase by small molecules has become a promising target in the treatment of cancer. Objective: In this study, we approached pharmacophore modeling coupled with a structure-based virtual screening workflow to identify the potent inhibitors. Methods: The top selected hit compounds have been rescored using the MM/GBSA approach. To understand the molecular reactivity, electronic properties, and stability of those inhibitors, we have employed density functional theory and molecular dynamics. Following that, the best 21 hit compounds have been further post-processed with a Quantum ligand partial charge-based rescoring process and further validated by implementing molecular dynamics simulation. Results: The ten hit compounds have been hypothesized and considered as potent inhibitors of VEGFR-2 tyrosine kinase. This study also signifies the contribution of QM-based ligand partial charge, which is more accurate in predicting reliable free binding energy and filtering large ligand libraries to hit optimization, rather than assigning those of the force field-based method. From the binding pattern analysis of all the complexes, amino acids, such as Glu885, Cys919, Cys1045, Thr916, Thr919, and Asp1046, were found to have comprehensive interaction with the hit compounds. Conclusion: Hence, this could prove to be useful as a potential inhibition site of the VEGFR-2 tyrosine kinase domain for future researchers. Moreover, this study also emphasizes the conformational changes upon ATP binding, based on either the receptor's rigidity or flexibility. [ABSTRACT FROM AUTHOR]

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC50 values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds 15a, 15b, and 15d showed IC50 from 17.39 to 47.10 µM against human cancer cell lines; hepatocellular carcinoma (HepG2), prostate cancer (PC3), and breast cancer (MCF-7). Meanwhile, the first in terms of VEGFR-2 inhibition was compound 15d which came second with regard to antitumor assay with IC50 = 24.10, 40.90, and 33.40 µM against aforementioned cell lines, respectively. Furthermore, Compound 15d increased apoptosis rate of HepG2 from 1.20 to 12.46% as it significantly increased levels of Caspase-3, BAX, and P53 from 49.6274, 40.62, and 42.84 to 561.427, 395.04, and 415.027 pg/mL, respectively. Moreover, 15d showed IC50 of 253 and 381 nM against HER2 and FGFR, respectively. [ABSTRACT FROM AUTHOR]

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns. [ABSTRACT FROM AUTHOR]