Vascular Endothelial Growth Factor Receptor Inhibitor Research Articles

Design of VEGFR2 Inhibitors: Construction and Screening of Virtual Compound Libraries

Objective: The current use of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors is often limited by low selectivity and adverse side effects, highlighting the urgent need for novel, highly selective agents targeting this receptor. Methods: Based on existing VEGFR-2 inhibitors, we employed computer-aided drug design (CADD) techniques to develop a virtual compound library using active docking fragments. Molecular docking was performed using the configuration of VEGFR-2 as the receptor protein(PDB:4ASD). Comparative analysis and screening identified the most promising inhibitor, which was subsequently validated through molecular dynamics simulations. Results:: From the virtual library, 10 potential highly active inhibitors were identified. In particular, Compound 9 demonstrated strong binding affinity with the protein configuration, forming four hydrogen bonds during docking. The calculated CODOCKER energy was 39.7315 kcal/mol, with an RMSD of 0.4634 nm and RMSF of 0.3234 nm. Compared to Sorafenib, Compound 9 exhibited superior docking selectivity and activity. Conclusion: Computational analyses suggest that Compound 9 is a promising candidate as a highly selective VEGFR-2 inhibitor. Nonetheless, due to the inherent limitations of in silico docking studies, further chemical synthesis and experimental biological validation are required to confirm its potential.

From bench to bedside: elucidating VEGF(R) inhibitor-related heart failure in cancer treatment

BackgroundVascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors play a pivotal role in treating various tumors; however, the clinical characteristics and molecular mechanisms of their associated heart failure (HF) remain incompletely understood.MethodsWe investigated the epidemiological characteristics of VEGF or VEGFR inhibitors [VEGF(R)i]-related heart failure (VirHF) using the global pharmacovigilance database Vigibase. The phenotypic features and molecular mechanisms of VirHF were characterized using VEGF(R)i-treated mouse models through a combination of echocardiography, histopathological analysis, and transcriptome sequencing. Furthermore, we performed a retrospective analysis of cardiac function parameters in patients undergoing VEGF(R)i treatment at local hospitals.ResultsIn the analysis of 1871 VirHF cases, elderly patients (≥ 65 years) and female subjects demonstrated an elevated risk of occurrence. Experimental studies in mice revealed that both acute and chronic VEGF(R)i administration resulted in reduced left ventricular EF, cardiomyocyte hypertrophy, and myocardial fibrosis. Transcriptomic analysis identified significant dysregulation of multiple key signaling pathways, including DNA repair (R = 0.46), mitochondrial ATP synthesis (R = 0.39), glycogen metabolism regulation (R = 0.45), and proteasome-mediated protein degradation (R = 0.45). Moreover, significant upregulation was observed in inflammatory pathways, specifically those involving IL-1, IL-6, TNF-α, and IRF3/IRF7-mediated immune responses. Clinical cohort analyses demonstrated significant elevations in both cardiac injury biomarkers (NT-proBNP, CK-MB, cTnT) and inflammatory mediators (CRP) following VEGF(R)i administration.ConclusionsOur findings present the first comprehensive characterization of VirHF clinical features and elucidate its underlying molecular mechanisms, thereby providing a theoretical framework for optimizing the clinical safety of VEGF(R)i therapy.

Dual VEGFR-2 and EGFRT790M inhibitors of phenyldiazenes: anticancer evaluations, ADMET, docking, design and synthesis.

New phenyldiazene scaffold-linked heterocyclic pyrazole, pyrimidinone, pyrimidinthione, and/or triazine rings have been developed and synthesized. Cytotoxicity of our derivatives was estimated on four cancer and VERO normal cell lines targeting EGFRT790M (epidermal growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) enzymes. Our new derivatives selectively inhibited both VEGFR-2 and EGFR as they have the essential structural requirements for inhibitors of both receptors. Derivative 14 was the most active on A549, HCT116, HepG2, and MCF-7 cancers with half-maximal inhibitory concentration (IC50) = 5.50, 9.77, 7.12, and 7.85 µM respectively. The assessed derivatives 5, 7, 8, 9, 10, 12 and 14 showed IC50 = 54.40-62.60 μM against normal VERO (normal kidney) cells with low toxicity. In addition, derivatives 14, 8, 10, 7 and 9 were discovered to be very good active inhibitors of VEGFR-2 at IC50 values of 1.15, 1.35, 140, 1.78 and 1.90 µM, respectively. Furthermore, derivatives 14, 10, 8, and 9 strongly repressed EGFRT790M with IC50 = 0.28, 0.33, 0.35, and 0.50 µM correspondingly. Additionally, the highly active compounds 8, 10, and 14 showed good ADMET profile. Our derivatives could be considered as anticancer agents with dual VEGFR-2 and EGFRT790M inhibition.

Advances in VEGFR Inhibitors: A Comprehensive Review of Novel Anticancer Agents.

Cancer, characterized by aberrant cell growth, presents a formidable health challenge, impacting millions of individuals worldwide each year. Among the myriad mechanisms facilitating tumor progression, Vascular Endothelial Growth Factor receptors (VEGFR) play a pivotal role in driving angiogenesis the process by which tumors develop their own blood supply. This vascularization not only supports tumor nourishment and growth but also facilitates metastasis, enabling cancer to spread to distant sites. VEGFR inhibitors offer a strategic approach to disrupt the VEGF-VEGFR binding pathway, thereby impeding angiogenesis, metastasis, and the proliferation of cancer cells. This review elucidates the latest advancements in medicinal chemistry pertaining to VEGFR inhibitors, showcasing a variety of chemical moieties and assessing their efficacy across different cancer cell lines. The novel compounds highlighted in this review exhibit significant promise for anticancer evaluation through targeted VEGFR kinase inhibition. A robust body of in vivo, in vitro, and ex vivo studies supports these findings, demonstrating the antitumor effects of these compounds. Computational analyses further enhance our understanding by predicting compound binding affinities, pharmacokinetics, and overall drug-likeness. Despite the significant progress made in developing effective VEGFR inhibitors, challenges remain in refining these agents for optimal cancer treatment. This review not only summarizes the advancements achieved in VEGFR inhibitor development but also emphasizes the ongoing hurdles that must be addressed to enhance the efficacy of cancer therapies.

Unraveling the power of peptides from Cucumaria frondosa coelomic fluid as multitarget therapy of diabetic kidney disease: An in-silico study

Diabetic kidney disease is a condition characterized by persistent albuminuria, diabetic glomerular lesions, and a reduced glomerular filtration rate in people with diabetes. Peptides in Cucumaria frondosa coelomic fluid have been proven to provide antidiabetic and anti-inflammatory activity that can be used as one of the innovations in developing a multitarget therapy, especially in diabetic kidney disease. Therefore, the aim of this study was to unravel the power of peptide-based metabolites from C. frondosa coelomic fluid as multitarget therapy for diabetic kidney disease using an in-silico study. UCSF Chimera software was utilized to construct the three-dimensional structure of coelomic fluid peptides from C. frondosa. The toxicity and allergenicity of peptides were examined using the ToxinPred and AllerTop websites, respectively. From the PDBJ database, the 3D structures of protein kinase B, alpha isoform (AKT1); vascular endothelial growth factor receptor 2 (VEGFR2); epidermal growth factor receptor (EGFR); α-glucosidase; and glucokinase were obtained. Molecular docking was carried out using MOE Software. In this in-silico study, peptide 9 (-10.32 kcal/mol), peptide 1 (-9.41 kcal/mol), and peptide 3 (-9.55 kcal/mol) were shown to act as specific adenosine triphosphate-competitive inhibitors of EGFR, AKT1, and VEGFR2, respectively. Peptide 8 (-11.06 kcal/mol) can specifically inhibit α-glucosidase by binding to its active site. Peptide 1 (-9.80 kcal/mol) is predicted to specifically inhibit glucokinase activity by blocking its active side. Molecular dynamics simulations confirmed stable interactions with receptor proteins. In conclusion, C. frondosa coelomic fluid peptides have been shown not only to alleviate diabetic kidney disease but also to stabilize blood glucose levels and prevent hyperglycemia based on in-silico analysis.

The positive feedback loop between SP1 and MAP2K2 significantly drives resistance to VEGFR inhibitors in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common and aggressive malignancies of the urinary system. Despite being the first-line treatment for advanced ccRCC, vascular endothelial growth factor receptor inhibitors (VEGFRis) face significant limitations due to both initial and acquired resistance, which impede complete tumor eradication. Using a CRISPR/Cas9 library screening approach, MAP2K2 was identified as a resistance-associated gene for three prevalent VEGFRis (Sunitinib, Axitinib, and Sorafenib). A strong positive correlation was observed between MAP2K2 expression and resistance to these VEGFRis. Drug-resistant cell lines established through dose-escalation consistently exhibited elevated MAP2K2 expression and activation of the MEK/ERK signaling pathway. Notably, combining MEK inhibitors (MEKis) with VEGFRis significantly enhanced the sensitivity of these resistant cells, leading to pronounced cell death. Additionally, a positive feedback regulatory mechanism was discovered between SP1 and MAP2K2, wherein SP1 and MAP2K2 could enhance mutual expression, thereby maintaining MEK/ERK pathway activation. This study reveals that MEKis can effectively re-sensitize VEGFRi-resistant cells, offering a promising therapeutic strategy for overcoming VEGFRi resistance in ccRCC.

Potential VEGFR2 inhibitors for managing metastatic cervical cancer: insights from molecular dynamics and free energy landscape studies.

Metastatic cervical cancer, the advanced stage where the cancer spreads beyond the cervix to other parts of the body, poses significant treatment challenges and is associated with poor survival rates. Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), a critical angiogenic mediator, is upregulated in metastatic cervical cancer, driving the formation of new blood vessels that fuel tumor growth and spread, making it an attractive target for anti-angiogenic therapies aimed at halting metastasis. This study aims to determine the anti-angiogenic effects of natural compounds to identify new VEGFR2 inhibitors for managing metastatic cervical cancer. The potential effect of these compounds as VEGFR2 inhibitors at the structural level was assessed using various methods such as virtual screening, docking, MD simulations (1000ns), binding free energy calculations, and free energy landscape analysis. Four compounds, including IMPHY007574, IMPHY004129, IMPHY008783, and IMPHY004928, were found to be potential VEGFR2 inhibitors. Among the structures analyzed in the present work, IMPHY007574 revealed the highest binding stability with VEGFR2 and the most favorable interaction pattern, thus proving the possibility of its use as an effective anti-angiogenic compound. The other three compounds also demonstrated a reasonably good promise in VEGFR2 inhibition. These findings provide a foundation for developing novel therapeutic strategies for metastatic cervical cancer, potentially overcoming drug resistance and improving patient survival rates.

Discovery of novel VEGFR2 inhibitors against non-small cell lung cancer based on fingerprint-enhanced graph attention convolutional network

Despite the proven inhibitory effects of drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2) on solid tumors, including non-small cell lung cancer (NSCLC), the development of anti-NSCLC drugs solely targeting VEGFR2 still faces risks such as off-target effects and limited efficacy. This study aims to develop a novel fingerprint-enhanced graph attention convolutional network (FnGATGCN) model for predicting the activity of anti-NSCLC drugs. Employing a multimodal fusion strategy, the model integrates a feature extraction layer that comprises molecular graph feature extraction and molecular fingerprint feature extraction. The performance evaluation results indicate that the model exhibits high accuracy and stability in predicting activity. Moreover, we explored the relationship between molecular features and biological activity through visualization analysis, thus improving the interpretability of the approach. Utilizing this model, we screened the ZINC database and conducted high-precision molecular docking, leading to the identification of 11 potential active molecules. Subsequently, molecular dynamics simulations and free energy calculations were performed. The results demonstrate that all 11 aforementioned molecules can stably bind to VEGFR2 under dynamic conditions. Among the short-listed compounds, the top six exhibited satisfactory inhibitory activity against VEGFR2 and A549 cells. Especially, compound Z-3 displayed VEGFR2 inhibitory with IC50 values of 0.88 μM, and anti-proliferative activity against A549 cells with IC50 values of 4.23 ± 0.45 μM. This approach combines the advantages of target-based and phenotype-based screening, facilitating the rapid and efficient identification of candidate compounds with dual activity against VEGFR2 and A549 cell lines. It provides new insights and methods for the development of anti-NSCLC drugs. Furthermore, further biological activity tests revealed that Z1-Z3 and Z6 manifested relatively strong antiproliferative activities against NCI-H23 and NCI-H460, and relatively low toxicity towards GES-1. The hit compounds were promising candidates for the further development of novel VEGFR2 inhibitors against NSCLC.

Development of axitinib-loaded polymeric ocular implants for the treatment of posterior ocular diseases.

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the primary causes of vision impairment and blindness worldwide. The current treatment for these diseases is an intravitreal injection of anti-VEGF agents, which are costly and require frequent injections. Implants can be used to sustain the release of drugs and minimize side effects. Axitinib (AX) is a potent VEGF receptor inhibitor and a promising candidate for treating posterior ocular diseases, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). A sustained release of AX was successfully achieved from 3D-printed AX-loaded implants fabricated using the well-known 3D printing technique, semi-solid extrusion (SSE). AX at concentrations of 10% w/w and 20% w/w was incorporated within the polycaprolactone (PCL) and Precirol®-based matrix. The fabricated implants were characterized via FTIR spectroscopy, SEM imaging, and thermal analysis. The implants were also evaluated for their drug release and biocompatibility. The AX-loaded implants exhibited thermal stability, and no chemical interactions were found between AX and the matrix components. The release mechanism study of AX revealed that the concentration of drug loading influenced AX release from the implant, with a 10% w/w and 20 %w/w of AX showing first-order and Korsmeyer-Peppas mechanism, respectively. A biocompatibility study using ARPE-19 cells confirmed that AX-loaded implants are nontoxic and safe for ocular use.

Synthesis and structural proof of novel oxazolo[5,4-d]pyrimidine derivatives as potential VEGFR2 inhibitors. In vitro study of their anticancer activity

The present study aimed to design and synthesize novel 6-N-benzyloxazolo[5,4-d]pyrimidin-7(6H)-imines 3a-j as possible inhibitors of the vascular endothelial growth factor receptor 2 (VEGFR2). The structures of newly synthesized compounds were confirmed via spectral and crystallographic data. NOESY spectroscopy was very useful in distinguishing between 6-N-benzyl-7(6H)-imine 3a and isomeric 7-N-benzyl-7-amine 4a, obtained by Dimroth rearrangement. Molecular docking at the VEGFR2 active site was performed, indicating that 7(6H)-imines should have a similar binding mode as type II VEGFR2 inhibitors. All derivatives were preliminary evaluated for in vitro cytotoxic activity against four human cancer cell lines, including lung cancer (A549), colorectal cancer (HT-29), melanoma (A375), breast cancer (MCF7), using tivozanib as a reference drug, and some of them were subjected to VEGFR2 inhibition, anti-angiogenic activity, and human serum albumin (HSA) binding assays. Only 6-N-2,4-dimethoxybenzyl derivative 3h appeared to be as active as tivozanib against all tested anticancer cell lines but equally toxic to healthy normal human dermal fibroblasts (NHDF). Derivatives 3f (6-N-2-methybenzyl) and 3b (6-N-4-methylbenzyl) have revealed slightly worse activity than 3h. They were cytotoxic agents comparable to tivozanib against three anticancer lines, but only 3b showed no cytotoxicity against NHDF. Both 3b and 3h proved to be effective VEGFR2 inhibitors with IC50 values comparable to that of tivozanib. Notably, 4a did not actually show an anticancer effect against the tested cancer lines, in contrast to isomeric 3a. In an angiogenesis assay, 3f and 3h significantly suppressed the tube formation ability of human dermal microvascular endothelial cells (HMEC-1), indicating their anti-angiogenic potential. The interactions between these compounds and HSA appeared to occur at two specific binding sites.

Targeting Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2): Latest Insights on Synthetic Strategies.

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.

Mineralocorticoid Receptor in Endothelial Cells Contributes to Vascular Endothelial Growth Factor Receptor Inhibitor-Induced Vascular and Kidney Damage.

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure (BP) via its effects on the vasculature and the kidney. Thus, we interrogated the role of the MR in EC dysfunction, renal impairment, and hypertension in a mouse model of VEGFRi-induced hypertension using sorafenib. EC dysfunction in mesenteric arterioles was assessed by immunoblotting for phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177. Renal damage was measured by assessing glomerular endotheliosis histologically. BP was measured using implanted radiotelemetry. Six days of sorafenib treatment significantly impaired mesenteric resistance vessel EC function, induced renal damage, and increased BP. Pharmacologic MR blockade with spironolactone prevented the sorafenib-induced decline in eNOS phosphorylation and renal glomerular endotheliosis, without affecting systolic BP (SBP) or diastolic BP. Mice with the MR knocked out specifically in ECs (EC-MR-KO) were protected from sorafenib-induced EC dysfunction and glomerular endotheliosis, whereas smooth muscle cell-specific MR (SMC-MR) knockout mice were not. Neither EC-MR nor SMC-MR knockout affected the degree to which sorafenib increased SBP or diastolic BP. These results reveal that the MR, specifically in EC but not in SMCs, is necessary for VEGFRi-induced renal and vascular injury. While ineffective at lowering SBP, these data suggest potential therapeutic benefits of MR antagonists, like spironolactone, to protect the vasculature and the kidneys from VEGFRi-induced injury.

New Thieno[2,3-d]pyrimidines as Anticancer VEGFR-2 Inhibitors with Apoptosis Induction: Design, Synthesis, and Biological and In Silico Studies.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a critical protein involved in tumor progression, making it an attractive target for cancer therapy. This study aimed to synthesize and evaluate novel thieno[2,3-d]pyrimidine analogues as potential anticancer VEGFR-2 inhibitors. The thieno[2,3-d]pyrimidine analogues were synthesized following the pharmacophoric features of VEGFR-2 inhibitors. The anticancer potential was assessed against PC3 and HepG2 cell lines. The VEGFR-2 inhibition was evaluated through IC50 determination. Cell cycle analysis and apoptosis assays were performed to elucidate the mechanisms of action. Molecular docking, molecular dynamics simulations, MM-GBSA, and PLIP studies were conducted to investigate the binding affinities and interactions with VEGFR-2. Additionally, in silico ADMET studies were performed. Compound 8b demonstrated significant anti-proliferative activities with IC50 values of 16.35 μM and 8.24 μM against PC3 and HepG2 cell lines, respectively, surpassing sorafenib and exhibiting enhanced selectivity indices. Furthermore, compound 8b showed an IC50 value of 73 nM for VEGFR-2 inhibition. Cell cycle analysis revealed G2-M phase arrest, while apoptosis assays demonstrated increased apoptosis in HepG2 cells. Molecular docking and dynamic simulations confirmed the binding affinity and interaction of compound 8b with VEGFR-2, supported by MMGBSA and PLIP studies. In silico ADMET studies indicated the drug development potential of the synthesized thieno[2,3-d]pyrimidines. The study highlights compound 8b as a promising VEGFR-2 inhibitor with potent anti-proliferative activities. Its mechanism of action involves cell cycle arrest and induction of apoptosis. Further, molecular docking and dynamic simulations support the strong binding affinity of compound 8b to VEGFR-2.

Repeated treatment with VEGF receptor inhibitors induces phenotypic changes in endothelial cells and pericytes in the rat retina

Abnormal ocular angiogenesis is a major cause of visual impairment and vision loss in neovascularization-related diseases. Currently, anti-vascular endothelial growth factor (VEGF) drugs are used to treat ocular neovascularization, but repeated injections are needed to maintain their therapeutic effects. However, repeated injection of anti-VEGF drugs may affect the retinal blood vessel phenotype and diminish therapeutic effects. In this study, we aimed to investigate the phenotypic changes in endothelial cells and pericytes caused by the repeated interruption of the VEGF receptor signaling pathway in neonatal rats. KRN633 (10 mg/kg), a VEGF receptor tyrosine kinase inhibitor, was subcutaneously administered on postnatal day (P)-7 and P8 (first round), P14 and P15 (second round), and P21 and P22 (third round). The rat eyes were collected on P7, P9, P14, P16, P21, P23, P28, and P35. Using retinal flat-mount specimens stained with specific markers for vascular endothelial cells, basement membranes, and pericytes, the arteriolar tortuosity, capillary area density, and distribution of pericytes were evaluated. Significant loss of capillaries was observed the day after the first round of KRN633 treatment, after which aggressive angiogenesis occurred, leading to the formation of tortuous arterioles. Rats that completed second and third rounds of KRN633 treatment showed more severe abnormalities in the retinal vasculature than those that only completed first round treatment. Repeated treatment with KRN633 decreased the anti-angiogenic effects but increased the immunoreactivity of α-smooth muscle actin in the pericytes on veins and capillaries. α-Smooth muscle actin expression was inversely correlated to anti-angiogenic effects. Overall, these results revealed that repeated interruption of VEGF receptor signaling pathway altered the phenotypes of endothelial cells and pericytes and induced anti-VEGF drug resistance. Therefore, careful follow-up is necessary when using anti-VEGF drugs to treat abnormal angiogenesis-associated ocular diseases.

Comprehensive analysis of VEGF/VEGFR inhibitor-induced immune-mediated hypertension: integrating pharmacovigilance, clinical data, and preclinical models.

This study aimed to elucidate the differential immunological mechanisms and characteristics of hypertension induced by VEGF inhibitors (VEGFi) and VEGF receptor inhibitors (VEGFRi), with the goal of optimizing monitoring strategies and treatment protocols. We investigated the risk of immune-related adverse events associated with VEGFi/VEGFRi-induced hypertension by analyzing the FDA Adverse Event Reporting System (FAERS) database. Findings were corroborated with blood pressure characteristics observed in clinical patients and preclinical models exposed to various VEGF/VEGFRi. Clinical and preclinical studies were conducted to compare immunological responses and hypertension profiles between inhibitor classes. An integrative analysis across cancer types and species was performed, focusing on key signaling pathways. Analysis of FAERS data, in conjunction with clinical observations, revealed that both VEGFi and VEGFRi significantly elevated the risk of immune-mediated, blood pressure-related adverse events (ROR=7.75, 95% CI: 7.76-7.95). Subsequent clinical and preclinical studies demonstrated differential immunological responses and hypertension profiles between inhibitor classes. VEGFRi exhibited a more rapid onset, greater blood pressure elevation, and higher incidence of immune-mediated adverse events compared to VEGFi (Systolic BP: ROR=0 for VEGFi vs. ROR=12.25, 95% CI: 6.54-22.96 for VEGFRi; Diastolic BP: ROR=5.09, 95% CI: 0.60-43.61 for VEGFi vs. ROR=12.90, 95% CI: 3.73-44.55 for VEGFRi). Integrative analysis across cancer types and species, focusing on key signaling pathways, revealed that VEGF/VEGFRi-induced blood pressure elevation was associated with immunomodulation of the mitogen activated protein kinase (MAPK) pathway (R=-0.379, P=0.0435), alterations in triglyceride metabolism (R=-0.664, P=0.0001), modulation of myo-inositol 1,4,5-trisphosphate-sensitive calcium release channel activity (R=0.389, P=0.0378), and dysregulation of nitric oxide eNOS activation and metabolism (R=-0.439, P=0.0179). The temporal dynamics of these effects demonstrated greater significance than dose-dependent responses. Both VEGFi and VEGFRi significantly augmented the risk of immune-mediated, blood pressure-related adverse events, with VEGFRi inducing a more rapid and pronounced onset of blood pressure elevation and a higher incidence of immune-related, blood pressure-associated adverse events compared to VEGFi.

Computer-Aided Design of VEGFR-2 Inhibitors as Anticancer Agents: A Review.

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.

7410 Bevacizumab Induced Hypothyroidism

Abstract Disclosure: A.L. McKenna: None. S. Thota-Kammili: None. K. Grennan: None. S. Rao: None. It is known that thyroid dysfunction is an adverse effect of tyrosine kinase inhibitors (TKIs) via inhibition of the vascular endothelial growth factor receptor (VEGFR). The VEGF signaling pathway is important in regulating angiogenesis in tumors and normal tissue. As a highly vascularized gland, it is expected the thyroid may be compromised because of VEGFR inhibitors. Proposed mechanisms of thyroid dysfunction include capillary regression and constriction leading to reduced vascular perfusion to the gland. Bevacizumab is a monoclonal antibody that targets VEGF and inhibits activation of VEGFR, reducing angiogenesis; interestingly, this is not commonly reported in the literature. Here we present a case where bevacizumab altered thyroid function in a patient with pre-existing primary hypothyroidism. A 60-year-old woman presented with worsening hypothyroidism. She reported a history of nonautoimmune primary hypothyroidism diagnosed in her early 20s; she still had an intact thyroid with no history of head/neck radiation. In the months leading to the presentation, she had been receiving maintenance chemotherapy with 5 fluorouracil and bevacizumab every 2 weeks for metastatic duodenal carcinoma. Prior to starting chemotherapy, she had been on a steady dose of 112 mcg of levothyroxine (LT4) daily. After 6 months on chemotherapy, she reported symptoms of fatigue and hair loss. Workup revealed an elevated TSH of 41 mIU/L (reference 0.3-4.2 mIU/L). She denied any significant changes in weight or malabsorption issues. Aside from the chemotherapy, no other new medications were introduced. Her LT4 dose was increased to 137 mcg daily, and 3 months later, there was improvement in TSH to 6.5 mIU/L as well as her symptoms. At this point, bevacizumab was briefly on hold for 2 months due to an upcoming procedure, hence there was no change to LT4 to avoid over correction. Her TSH normalized and was trending lower while bevacizumab was on hold. Once bevacizumab resumed, LT4 was preemptively increased to 150 mcg daily. Four months after resuming bevacizumab, her TSH remains within the normal reference range on 150 mcg LT4. It is hypothesized that this VEGF blocker led to worsening of her underlying hypothyroidism.Given the shared down regulation in the VEGF signaling pathway, it would be expected that TKIs and monoclonal antibodies against VEGF would share similar adverse reactions to the thyroid. However, to our knowledge, there have been limited reports of bevacizumab induced thyroid dysfunction in the literature. Explanations to this may include the more targeted VEGF inhibition with bevacizumab versus the inhibition of multiple kinase receptors from the TKIs. Further research into this will be needed. This case demonstrates that bevacizumab can impact thyroid function and thyroid labs may need to be monitored at the onset and during VEGF inhibitor therapies. Presentation: 6/3/2024

The expression level of VEGFR2 regulates mechanotransduction, tumor growth and metastasis of high grade serous ovarian cancer cells

Recent data shows that alterations in the expression and/or activation of the vascular endothelial growth factor receptor 2 (VEGFR2) in high grade serous ovarian cancer (HGSOC) modulate tumor progression. However, controversial results have been obtained, showing that in some cases VEGFR2 inhibition can promote tumorigenesis and metastasis. Thus, it is urgent to better define the role of the VEGF/VEGFR2 system to understand/predict the effects of its inhibitors administered as anti-angiogenic in HGSOC. Here, we modulated the expression levels of VEGFR2 and analyzed the effects in two cellular models of HGSOC. VEGFR2 silencing (or its pharmacological inhibition) promote the growth and invasive potential of OVCAR3 cells in vitro and in vivo. Consistent with this, the low levels of VEGFR2 in OV7 cells are associated with more pronounced proliferative and motile phenotypes when compared to OVCAR3 cells, and VEGFR2 overexpression in OV7 cells inhibits cell growth. In vitro data confirmed that VEGFR2 silencing in OVCAR3 cells favors the acquisition of an invasive phenotype by loosening cell-ECM contacts, reducing the size and the signaling of focal adhesion contacts (FAs). This is translated into a reduced FAK activity at FAs, ECM-dependent alterations of mechanical forces through FAs and YAP nuclear translocation. Together, the data show that low expression, silencing or inhibition of VEGFR2 in HGSOC cells alter mechanotransduction and lead to the acquisition of a pro-proliferative/invasive phenotype which explains the need for a more cautious use of anti-VEGFR2 drugs in ovarian cancer.

New Anti-Angiogenic Therapy for Glioblastoma With the Anti-Depressant Sertraline.

Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications. The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. Invivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs invitro and 005 mouse models invivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability.

Inhibitory Effect of Phenolic Compounds on Vascular Endothelial Growth Factor-Induced Retinal Endothelial Permeability and Angiogenesis.

Age-related macular degeneration (AMD), often triggered by endothelial barrier disruption through vascular endothelial growth factor (VEGF), is a leading cause of blindness. This study investigated the inhibitory effects of phenolic compounds on VEGF-induced endothelial cell proliferation, migration, angiogenesis, and permeability using human retinal microvascular endothelial cells (hRECs). Thirty-seven polyphenolic compounds were selected from various databases based on their antioxidant properties, abundance in food, and solubility. These compounds significantly reduced migration, tube formation, and endothelial permeability in VEGF-stimulated hRECs. Notably, formononetin, eriodictyol, biochanin A, and p-coumaric acid were more effective in suppressing VEGF-induced angiogenesis and endothelial permeability than lutein. Molecular docking simulations revealed that formononetin, eriodictyol, and biochanin A had relatively lower binding energies with VEGF receptor 2 (VEGFR2) than lutein and sorafenib. These findings highlight the potential of phenolic compounds to be used as VEGFR2 inhibitors and an alternative strategy for preventing AMD.