SU5416​

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

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
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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.).
Cell Type
Cancer Cells and Cell Lines
Species
Human, Mouse, Non-Human Primate, Other, Rat
Area of Interest
Angiogenic Cell Research, Cancer, Disease Modeling, Immunology
CAS Number
204005-46-9
Chemical Formula
C₁₅H₁₄N₂O
Purity
≥ 98%
Pathway
Tyrosine Kinase
Target
ABL, ALK, FLT-3, KDR, KIT, PDGFR, RET

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Product Name
SU5416​
Catalog #
73444, 73442
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
SU5416​
Catalog #
73444, 73442
Lot #
All
Language
English

Resources and Publications

Publications (5)

SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction. de Raaf MA et al. The European respiratory journal 2014

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.
Severe pulmonary arterial hypertension induced by SU5416 and ovalbumin immunization. Mizuno S et al. American journal of respiratory cell and molecular biology 2012

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.
Inhibition of RET tyrosine kinase by SU5416. Mologni L et al. Journal of molecular endocrinology 2006

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.