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Catalog No.GC15307

SU5416 Chemical Structure

SU5416 is a potent small molecule vascular endothelial growth factor receptor (VEGFR) inhibitor.

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10mM (in 1mL DMSO)
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Cell experiment [1]:

Cell lines

Human microvascular endothelial cells of the lung-blood (HMVEC-LBl)

Preparation Method

Cells were plated into 24-well plates and grown to confluence in EGM-2MV medium containing 2.5% FBS plus supplements. Only cells in passage 5 were used, with n = 12 wells per experimental condition.

Reaction Conditions

HMVEC-LBl was exposed to human VEGF-121 (40 ng/mL) in-vitro in serum-free medium for 7 h, in the absence or presence of the VEGF receptor antagonist, SU5416 (3 and 10 μM).


SU5416 can block the effects of VEGF and completely prevent VEGFR2 phosphorylation as well. There was no evidence of background VEGFR2 phosphorylation in the HMVEC-LBl and in serum-free medium. Adding SU5416 did not affect the background phosphorylation. In the absence of VEGF, SU5416 increased ET-1 production, by 16% at 10 μM, and SU5416 can completely abolish the VEGF effect on ET-1 production.

Animal experiment [2]:

Animal models

Wild-type C57BL/6 mice (male, 8–10 weeks, 20–24 g) and genetically engineered TLR4-deficient mice (male, 8–10 weeks, 20–22 g)

Preparation Method

Mice were stimulated by intratracheal administration of LPS after anesthetization with an intraperitoneal (i.p.) injection of tribromoethanol. Isopyknic saline-treated mice served as blank control group. After LPS stimulation, the experimental mice were treated with SU5416, DXM or DXM + SU5416 by oral administration for 12 hours. DXM-treated mice were served as positive control group.

Dosage form

20 mg/kg, BW solution in DMSO


SU5416 could be implemented to suppress immune response in mice with ALI. Normally, excessive activation and penetration of neutrophils is the common pathological process in LPS-induced ALI. Which subsequently enhanced the release of proinflammatory cytokines, which can further aggravate lung injury. SU5416 exhibited inhibitory effect on the population of neutrophil cell (P


[1]. Star GP, et al. Effects of vascular endothelial growth factor on endothelin-1 production by human lung microvascular endothelial cells in vitro. Life Sci. 2014 Nov 24;118(2):191-4.

[2]. Huang X, et al. SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells. Drug Des Devel Ther. 2019 May 23;13:1763-1772.


SU5416 is a potent small molecule vascular endothelial growth factor receptor (VEGFR) inhibitor. SU5416 is a 3-substituted indolin-2-one compound with relatively high specificity for VEGFR-2 and VEGFR-1, used extensively in animal models of PH, primarily due to effects on pulmonary vascular endothelial cell apoptosis and proliferation.[1] SU416 has been developed for the treatment of solid human tumors as well. [3]

In vitro study was performed to examine the inhibitory effect of SU5416 on KDR phosphorylation. Which indicated that pretreatment of BCECs with SU5416 resulted in a dose-dependent inhibition of KDR phosphorylation with an IC50 of 0.29 ± 0.071 µM (n=6) SU5416 almost completely inhibited KDR phosphorylation at the concentration of 3 µM. Few BCECs were stained with trypan blue after the treatment of SU5416, at least up to the concentration of 3 µM for 24 h. This suggested that the inhibitory effect of SU5416 on KDR phosphorylation was not due to the cell toxicity.[2]

In vivo study demonstrated that SU5416 could significantly reverse LPS-induced ALI in mice, and exert better protective effect in TLR4 knockout mice. SU5416 could also act as a protective agent against LPS-induced ALI in mice. Moreover, SU5416 dramatically restored the reduction of CD31 expression mediated by LPS, suggesting SU5416 could rescue LPS-induced dysfunction of pulmonary endothelial barrier. In addition, both p-VEGFR2 and VEGFR2 expressions were inhibited by SU5416 in WT and TLR4−/- mice. SU5416 could attenuate LPS-induced ALI through modulating the VEGF/VEGFR and NF-κB pathways, which suggested SU5416 might be used for the treatment of patients with inflammation-mediated ALI.[3]

[1]. Peloquin GL, et al. SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model. Respir Res. 2019 Jun 17;20(1):123.
[2] Takeda A, et al. Suppression of experimental choroidal neovascularization utilizing KDR selective receptor tyrosine kinase inhibitor. Graefes Arch Clin Exp Ophthalmol. 2003 Sep;241(9):765-72.
[3]. Huang X, et al. SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells. Drug Des Devel Ther. 2019 May 23;13:1763-1772.

Chemical Properties

Cas No. 204005-46-9 SDF
Synonyms Semaxinib;SU-5416;SU 5416
Chemical Name (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one
Canonical SMILES CC1=CC(=C(N1)C=C2C3=CC=CC=C3NC2=O)C
Formula C15H14N2O M.Wt 238.28
Solubility ≥ 11.9 mg/mL in DMSO Storage Desiccate at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

SU5416 plus hypoxia but not selective VEGFR2 inhibition with cabozantinib plus hypoxia induces pulmonary hypertension in rats: potential role of BMPR2 signaling

Pulm Circ2021 Jun 9;11(3):20458940211021528.PMID: 34178306DOI: 10.1177/20458940211021528

SU5416 plus chronic hypoxia causes pulmonary arterial hypertension in rats and is assumed to occur through VEGFR2 inhibition. Cabozantinib is a far more potent VEGFR2 inhibitor than SU5416. Therefore, we hypothesized that cabozantinib plus hypoxia would induce severe pulmonary arterial hypertension in rats. Cell proliferation and pharmacokinetic studies were performed. Rats were given SU5416 or cabozantinib subcutaneously or via osmotic pump and kept hypoxic for three weeks. Right ventricular systolic pressure and hypertrophy were evaluated at days 14 and 28 following removal from hypoxia. Right ventricular fibrosis was evaluated with Picro-Sirius Red staining. Kinome inhibition profiles of SU5416 and cabozantinib were performed. Inhibitor binding constants of SU5416 and cabozantinib for BMPR2 were determined and Nanostring analyses of lung mRNA were performed. Cabozantinib was a more potent VEGFR inhibitor than SU5416 and had a longer half-life in rats. Cabozantinib subcutaneous plus hypoxia did not induce severe pulmonary arterial hypertension. Right ventricular systolic pressure at 14 and 28 days post-hypoxia was 36.8 ± 2.3 mmHg and 36.2 ± 3.4 mmHg, respectively, versus 27.5 ± 1.5 mmHg in normal controls. For cabozantinib given by osmotic pump during hypoxia, right ventricular systolic pressure was 40.0 ± 3.1 mmHg at 14 days and 27.9 ± 1.9 mmHg at 28 days post-hypoxia. SU5416 plus hypoxia induced severe pulmonary arterial hypertension (right ventricular systolic pressure 61.9 ± 6.1 mmHg and 64.9 ± 8.4 mmHg at 14 and 28 days post-hypoxia, respectively). Cabozantinib induced less right ventricular hypertrophy (right ventricular free wall weight/(left ventricular free wall weight + interventricular septum weight) at 14 days post-hypoxia compared to SU5416. Right ventricular fibrosis was more extensive in the SU5416 groups compared to the cabozantinib groups. SU5416 (but not cabozantinib) inhibited BMPR2. Nanostring analyses showed effects on pulmonary gene expression of BMP10 and VEGFR1 in the SU5416 28 days post-hypoxia group. In conclusion, selective VEGFR2 inhibition using cabozantinib plus hypoxia did not induce severe pulmonary arterial hypertension. Severe pulmonary arterial hypertension due to SU5416 plus hypoxia may be due to combined VEGFR2 and BMPR2 inhibition.

SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model

Respir Res2019 Jun 17;20(1):123.PMID: 31208454DOI: 10.1186/s12931-019-1079-x

Background: Right ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a "master regulator" of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH.
Methods: C57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle.
Result: SU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis.
Conclusions: These findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.

SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells

Drug Des Devel Ther2019 May 23;13:1763-1772.PMID: 31213766DOI: 10.2147/DDDT.S188858

Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI. Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4-/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function. Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4-/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro. Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.

The effects of antiangiogenic compound SU5416 in a rat model of pulmonary arterial hypertension

Respiration2011;81(3):253-61.PMID: 21116108DOI: 10.1159/000322011

Several lines of evidence indicate that vascular endothelial growth factor (VEGF) plays a prosurvival and antiapoptotic role in endothelial cells. SU5416 is the first VEGF receptor 2 inhibitor to enter clinical development for cancer therapy. A phase I/II study of SU5416 has been completed, and the results show that SU5416 is well tolerated in patients with terminal cancers. It has been shown that VEGF receptor blockade using SU5416 combined with chronic hypoxia results in severe angioproliferative pulmonary hypertension (PAH) with neointimal changes in adult rats. Although classic animal models of pulmonary hypertension (that is, the monocrotaline and hypoxic models) do not form obstructive intimal lesions in the peripheral pulmonary arteries, the SU5416 model has shown pulmonary arterial changes resembling plexiform lesions. Therefore, the SU5416 model of PAH has been used for some time, and it has thus contributed to a better understanding of the pulmonary hypertensive process. However, the mechanism by which SU5416 combined with chronic hypoxia can result in PAH with plexiform-like lesions in adult rats is complex and still remains to be fully elucidated. The most likely explanation is that there is increased apoptosis of endothelial cells in response to the loss of the survival signaling, creating conditions favoring the emergence of apoptosis-resistant cells with increased growth potential, that is, the endothelial cell hyperproliferation that might characterize the plexiform lesions of human PAH. The aim of the present review is to provide information useful for understanding a potent inhibitor of VEGF receptor tyrosine kinase, SU5416, and to better understand its use for generating animal models of PAH.

Fasudil Dichloroacetate Alleviates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension by Ameliorating Dysfunction of Pulmonary Arterial Smooth Muscle Cells

Drug Des Devel Ther2021 Apr 22;15:1653-1666.PMID: 33935492DOI: 10.2147/DDDT.S297500

Background: Pulmonary arterial hypertension (PAH) is an incurable disease that urgently needs therapeutic approaches. Based on the therapeutic effects of fasudil and dichloroacetate (DCA) on PAH, we aimed to explore the effects and potential mechanism of a new salt, fasudil dichloroacetate (FDCA), in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH.
Methods: The rat model of PAH was established by a single subcutaneous injection of SU5416 (20 mg/kg) followed by hypoxia (10% O2) exposure for 3 weeks. FDCA (15, 45, or 135 mg/kg i.g. daily) or the positive control, bosentan (100 mg/kg i.g. daily), were administered from the first day after SU5416 injection. After 3-week hypoxia, hemodynamic parameters, and histological changes of the pulmonary arterial vessels and right ventricle (RV) were assessed. Additionally, in vitro, the effects of FDCA (50 μM), compared with equimolar doses of fasudil, DCA, or fasudil+DCA, on the proliferation, migration, and contraction of human pulmonary arterial smooth muscle cell (PASMC) under hypoxia (1% O2) were evaluated.
Results: FDCA dose-dependently attenuated SuHx-induced PAH, with significant reductions in RV systolic pressure, pulmonary artery wall thickness, pulmonary vessel muscularization, perivascular fibrosis, as well as RV hypertrophy and fibrosis. In vitro, FDCA inhibited hypoxia-induced PASMC proliferation, migration, and contraction to a greater degree than fasudil or DCA alone by restoring mitochondrial function, reducing intracellular Ca2+, and inhibiting calcium/calmodulin-dependent kinase (Ca2+/CaMK) activity as well as Rho-kinase activity.
Conclusion: FDCA ameliorates hypoxia-induced PASMC dysfunction by inhibiting both Ca2+/CaMK and Rho-kinase signaling pathways, as well as maintaining mitochondrial homeostasis, thus alleviating SuHx-induced PAH.


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