SU5416​

Tyrosine kinase inhibitor; Inhibits of KDR, PDGFR, KIT, RET, FLT-3, ABL and ALK

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Tyrosine kinase inhibitor; Inhibits of KDR, PDGFR, KIT, RET, FLT-3, ABL and ALK
From: 173 USD

Overview

SU5416 is a tyrosine kinase inhibitor best known as an ATP-competitive inhibitor of the kinase insert domain (KDR/VEGFR2/FLK1). In addition to inhibiting KDR (IC₅₀ = 1 μM), SU5416 also inhibits PDGFR (IC₅₀ = 20 μM), KIT (IC₅₀ = 30 nM), RET (IC₅₀ = 170 nM), FLT-3 (IC₅₀ = 160 nM), ABL (IC₅₀ = 11 μM), and ALK (IC₅₀ = 1.2 μM). SU5416 does not inhibit EGFR or FGFR tyrosine kinases (IC₅₀ > 100 μM; Fong et al.; Litz; Mologni et al.).

CANCER RESEARCH
· Prevents angiogenesis, thereby inhibiting tumor growth, catalysis and vascularization for a variety of cancers (Litz; Fong et al.).
· Inhibits RET-mediated transformation of NIH-3T3 mouse fibroblasts and Ba/F3 mouse pro-B cells (Mologni et al.).

DISEASE MODELING
· Causes pulmonary hypertension in SuHx rat model of pulmonary arterial hypertension, when combined with hypoxia (de Raaf et al.; Mizuno et al.).

IMMUNOLOGY
· Inhibits TGFβ1 activation and delays wound healing in rats (Haroon et al.).
Alternative Names:
NSC 696819; Semaxinib; Sugen 5416; VEGFR 2 Kinase Inhibitor
CAS Number:
204005-46-9
Chemical Formula:
C₁₅H₁₄N₂O
Molecular Weight:
238.3 g/mol
Purity:
≥ 98%
Pathway:
Tyrosine Kinase
Target:
ABL; ALK; FLT-3; KDR; KIT; PDGFR; RET

Scientific Resources

Product Documentation

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Educational Materials

(4)

Data and Publications

Publications

(5)
The European respiratory journal 2014

SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction.

de Raaf MA et al.

Abstract

The SU5416 combined with hypoxia (SuHx) rat model features angio-obliterative pulmonary hypertension resembling human pulmonary arterial hypertension. Despite increasing use of this model, a comprehensive haemodynamic characterisation in conscious rats has not been reported. We used telemetry to characterise haemodynamic responses in SuHx rats and associated these with serial histology. Right ventricular systolic pressure (RVSP) increased to a mean±sd of 106±7 mmHg in response to SuHx and decreased but remained elevated at 72±8 mmHg upon return to normoxia. Hypoxia-only exposed rats showed a similar initial increase in RVSP, a lower maximum RVSP and near-normalisation of RVSP during subsequent normoxia. Progressive vascular remodelling consisted of a four-fold increase in intima thickness, while only minimal changes in media thickness were found. The circadian range in RVSP provided an accurate longitudinal estimate of vascular remodelling. In conclusion, in SuHx rats, re-exposure to normoxia leads to a partial decrease in pulmonary artery pressure, with persisting hypertension and pulmonary vascular remodelling characterised by progressive intima obstruction.
American journal of respiratory cell and molecular biology 2012

Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization.

Mizuno S et al.

Abstract

The combination of chronic hypoxia and treatment of rats with the vascular endothelial growth factor (VEGF) receptor blocker, SU5416, induces pulmonary angio-obliteration, resulting in severe pulmonary arterial hypertension (PAH). Inflammation is thought to contribute to the pathology of PAH. Allergic inflammation caused by ovalbumin (OVA) immunization causes muscularization of pulmonary arteries, but not severe PAH. Whether disturbance of the immune system and allergic inflammation in the setting of lung endothelial cell apoptosis causes PAH is unknown. We investigated the effects of OVA-allergic inflammation on the development of PAH initiated by VEGF blockade-induced lung endothelial cell apoptosis. OVA-immunized rats were treated with SU5416 to induce pulmonary vascular endothelial cell apoptosis. The combination of OVA and SU5416 treatment resulted in severe angio-obilterative PAH, accompanied by increased IL-6 expression in the lungs. c-Kit(+) and Sca-1(+) cells were found in and around the lung vascular lesions. Pan-caspase inhibiton, dexamethasone treatment, and depletion of B-lymphocytes using an anti-CD20 antibody suppressed this remodeling. OVA immunization also increased lung tissue hypoxia-induced factor-1α and VEGF expression. Our results also suggest that the increased expression of hypoxia-induced factor-1α and IL-6 induced by the allergic lung inflammation may be a component of the pathogenesis of PAH.
Journal of molecular endocrinology 2006

Inhibition of RET tyrosine kinase by SU5416.

Mologni L et al.

Abstract

Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.
Lung Cancer 2004

The multi-targeted kinase inhibitor SU5416 inhibits small cell lung cancer growth and angiogenesis, in part by blocking Kit-mediated VEGF expression

J LITZ

Abstract

SU5416 is a multi-targeted kinase inhibitor that potentially has the ability to directly block tumor growth by inhibiting Kit signaling, as well as blocking angiogenesis by inhibiting vascular endothelial growth factor receptor (VEGFR) signaling. Previous work has demonstrated that SU5416 efficiently blocks Kit-mediated growth of small cell lung cancer (SCLC) in vitro. To determine the drug's effect on in vivo growth of SCLC, we studied its activity, alone and in combination with carboplatin, in chemotherapy-resistant H526, and chemotherapy-sensitive H209 murine xenograft models. SU5416 efficiently inhibited Kit activity in vivo when administered on a twice-weekly schedule. When administered over a 3-week period to animals bearing established tumors, it inhibited growth by at least 70%. It was at least as effective as carboplatin in suppressing growth of H526 xenografts. However, the combination with carboplatin was not superior to the most active single agent in either xenograft model at the doses and schedule utilized. SU5416 clearly inhibited growth in part by inhibiting angiogenesis, with microvessel density dropping by approximately 50% in treated xenografts. In addition to the recognized mechanism of inhibition of VEGFR, we uncovered a novel mechanism of angiogenesis suppression by demonstrating reduced VEGF expression in SU5416-treated xenografts. In vitro, stem cell factor treatment of the H526 cell line enhanced expression of VEGF, which was efficiently blocked with SU5416. Thus, we have demonstrated that SU5416 can inhibit SCLC growth by directly inhibiting tumor cell proliferation and by inhibiting angiogenesis, in part by inhibiting Kit-mediated VEGF expression. These data suggest that kinase inhibitors that target both Kit and VEGFR could play an important role in the treatment of SCLC, as well as other malignancies that express Kit.
Cancer research 1999

SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.

Fong TA et al.

Abstract

SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.
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