Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Wang, Lei; Liu, Wang-Qing; Broussy, Sylvain; Han, Bingnan; Fang, Hongming

doi:10.3389/fphar.2023.1307860

Cited by 17 publications

(2 citation statements)

References 220 publications

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“…Targeting VEGFR tyrosine kinase (TK) with multiple or specific kinase inhibitors presents another opportunity considering the number of already-approved drugs (sorafenib, suntinib, vandetanib, axitinib, cabozantinib, regorafenib, apatinib, nindetinib, lenvatinibanlotinib, fruquintinib, and tivozantinib) ( Figure 5 ). These drugs have different targets, and some are specific for VEGFR 1/2/3, such as axitinib, fruquintinb, and tivazantinib, while others target other tyrosine kinases besides VEGFR, such as c-Kit, FLT3, PDGFR-α/β, RET, FGFR-1/3, and others [ 46 ].…”

Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

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Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO

Srkalovic,

Nijim,

Srkalovic

et al. 2024

Biomedicines

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TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future.

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Section: Conclusion and Future Research Directionsmentioning

confidence: 99%

“…Reproduced with permission from Wang, L., Liu, W-Q., Broussy, S. Han, B. and Fang H. Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis. Front Pharmacol, 2024, 14, 1307860, doi: 10.3389/fphar.2023.1307860 [ 46 ].…”

Section: Figurementioning

confidence: 99%

Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO

Srkalovic,

Nijim,

Srkalovic

et al. 2024

Biomedicines

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Inhibitory effects of Gracilaria edulis and Gracilaria salicornia against the MGMT and VEGFA biomarkers involved in the onset and advancement of glioblastoma using in silico and in vitro approaches

Vasudevan,

Rangaraj,

Ramesh

et al. 2024

Biotech and App Biochem

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Glioblastoma (GBM), an aggressive primary brain tumor originating from glial cells, poses significant treatment challenges due to its rapid growth and invasiveness. The exact mechanisms of GBM's brain damage remain unclear. This study examines primary molecular markers commonly assessed in GBM patients, including brain‐derived neurotrophic factor (BDNF), platelet‐derived growth factor receptor A (PDGFRA), O6‐methylguanine DNA methyltransferase (MGMT), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor A (VEGFA) using computational approaches. The study revealed significant differences (p ≤ 0.05) in PDGFRA, EGFR, and VEGFA expression rates, which are particularly interesting. Additionally, MGMT and VEGFA showed higher hazard ratios. Expression levels of MGMT and VEGFA were visualized in immune and malignant cells using single‐cell RNA datasets GSE103224 and GSE148842. From a total of 48 compounds in Gracilaria edulis and 86 in Gracilaria salicornia, we identified 15 compounds capable of crossing the blood‐brain barrier. Notably, 2‐tridecanone (binding affinity [BA] = −4.2 kcal/mol; root mean square deviation [RMSD] = 1.479 Å) and decanoic acid, ethyl ester (BA = −4.2 kcal/mol; RMSD = 1.702 Å) from G. edulis interacted with MGMT via hydrogen bonds. The compound alpha‐terpineol interacted with MGMT (BA = −5.7 kcal/mol; RMSD = 0.501 Å) and VEGFA (BA = −4.7 kcal/mol; RMSD = 2.483 Å). Ethanolic and methanolic extracts from G. edulis and G. salicornia demonstrated mild anti‐cell proliferation properties in the GBM LN‐229 cell line, suggesting potential therapeutic benefits. This study highlights the significance of molecular markers and natural compounds in understanding and potentially treating GBM.

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Design, Development of Pyrazole‐Linked Spirocyclopropyl Oxindole‐Carboxamides as Potential Cytotoxic Agents and Type III Allosteric VEGFR‐2 Inhibitors

Valapil,

Devabattula,

Sakla

et al. 2024

ChemMedChem

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Tumor progression depends on angiogenesis, which is stimulated by growth factors like VEGF, targeting VEGFR kinase with small molecules is an effective anti‐angiogenic therapeutic approach. Sunitinib was rationally modified to spirocyclopropyloxindoline carboxamides and their in vitro cytotoxic profiling were evaluated. The molecular modelling studies enabled the screening of designed analogues and identified possible interactions within the type III allosteric inhibitor binding site of VEGFR‐2. The biological screening of compounds 15a‐y, revealed the ability of compound 15w to inhibit the cell growth in MCF‐7 cells with IC50 value of 3.87 ± 0.19 μM and alongside inhibition of VEGFR‐2 kinase at a IC50 concentration of 4.34 ± 0.13 μM was observed. VEGFR‐2 inhibition was validated through HUVEC tube formation inhibition assay. 15w also inhibited cell migration in wound healing assay. The qualitative assessment of apoptosis induction by 15w in MCF‐7 cells was evaluated through AO/EB and DAPI staining studies, whereas apoptotic quantification and cell cycle analysis were performed through FACS analysis. The current study strives to sequentially optimize the structural attributes of 3‐alkenyl oxindole core to surpass the existing challenges of well‐known VEGFR‐2 inhibitors and compound 15w was identified to be a prominent lead towards the development of clinical drug candidates

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Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Cited by 17 publications

References 220 publications

Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO

Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO

Inhibitory effects of Gracilaria edulis and Gracilaria salicornia against the MGMT and VEGFA biomarkers involved in the onset and advancement of glioblastoma using in silico and in vitro approaches

Design, Development of Pyrazole‐Linked Spirocyclopropyl Oxindole‐Carboxamides as Potential Cytotoxic Agents and Type III Allosteric VEGFR‐2 Inhibitors

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