KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth

Nakamura, Kazuhide; Yamamoto, Atsushi; Kamishohara, Masaru; Takahashi, Kohei; Taguchi, Eri; Miura, Tsuyoshi; Kubo, Kazuo; Shibuya, Masabumi; Isoe, Toshiyuki

doi:10.1158/1535-7163.1639.3.12

Cited by 59 publications

(4 citation statements)

References 36 publications

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“…Additionally, the potential involvement of other growth-factor-activated receptor tyrosine kinases (RTKs) was studied. The dual platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) inhibitor KRN633 (1 μM) , was used in these experiments to determine whether transactivation by these receptors was involved in the GDNF signaling. The structures and targets of the inhibitors used are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

“… a Refs and . b Refs and . c Refs and . d Refs − . e Refs and . PLCγ, phospholipase C; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; MEK-1/2, mitogen-activated protein kinase kinase; FGFR-1, fibroblast growth factor receptor 1; FGFR-3, fibroblast growth factor receptor 3; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor. …”

Section: Resultsmentioning

confidence: 99%

“…Simple colorometric detection can be used to measure the amount of LDH present in conditioned media, which directly correlates with the integrity of the cell membrane and, therefore, with cell health . Another measure of cell viability is the WST-1 cell assay, which measures cell viability or cytotoxicity using colorometric detection of a formazan dye that forms as a result of intact, metabolizing mitochondria . These two assays were used together to identify the cytotoxic effects, if any, occurring concurrently with GDNF release.…”

Section: Resultsmentioning

confidence: 99%

“…63 Another measure of cell viability is the WST-1 cell assay, which measures cell viability or cytotoxicity using colorometric detection of a formazan dye that forms as a result of intact, metabolizing mitochondria. 62 These two assays were used together to identify the cytotoxic effects, if any, occurring concurrently with GDNF release.…”

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confidence: 99%

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Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound

et al. 2015

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Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCγ in C6 glioma cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound

et al. 2015

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KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice

Abe

Nakahara

Morita

et al. 2013

Birth Defects Research Pt B

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We previously reported that treatment with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, during mid-pregnancy caused intrauterine growth restriction resulting from impairment of blood vessel growth in the labyrinthine zone of the placenta and fetal organs. However, the relative sensitivities of blood vessels in the placenta and fetal organs to vascular endothelial growth factor (VEGF) inhibitors have not been determined. In this study, we aimed to examine the effects of KRN633 on the vasculatures of organs in mother mice and their newborn pups by immunohistochemical analysis. Pregnant mice were treated daily with KRN633 (5 mg/kg) either from embryonic day 13.5 (E13.5) to E17.5 or from E13.5 to the day of delivery. The weights of the pups of KRN633-treated mice were lower than those of the pups of vehicle-treated mothers. However, no significant difference in body weight was observed between the vehicle- and KRN633-treated mice. The vascular development in the organs (the pancreas, kidney, and intestine) and intestinal lymphatic formation of the pups of KRN633-treated mothers was markedly impaired. In contrast, the KRN633 treatment showed no significant effect on the vascular beds in the organs, including the labyrinthine zone of the placenta, of the mother mice. These results suggest that blood vessels in fetal organs are likely to be more sensitive to reduced VEGF signaling than those in the mother. A partial loss of VEGF function during pregnancy could suppress vascular growth in the fetus without affecting the vasculature in the mother mouse, thereby increasing the risk of intrauterine growth restriction.

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Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups

Morita¹,

Nakahara²,

Abe³

et al. 2014

Birth Defects Research Pt B

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We previously reported that treatment of mid-pregnant mice with KRN633, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, caused fetal growth restriction resulting from diminished vascularization in the placenta and fetal organs. In this study, we examined how the treatment of mid-pregnant mice with KRN633 affects the development and morphology of vascular components (endothelial cells, pericytes, and basement membrane) in the retinas of their newborn pups. Pregnant mice were treated with KRN633 (5 mg/kg) once daily from embryonic day 13.5 until the day of delivery. Vascular components were examined using immunohistochemistry with specific markers for each component. Radial vascular growth in the retina was slightly delayed until postnatal day 4 (P4) in the newborn pups of KRN633-treated mothers. On P8, compared with the pups of control mothers, the pups of KRN633-treated mothers exhibited decreased numbers of central arteries and veins and abnormal branching of the central arteries. No apparent differences in pericytes or basement membrane were observed between the pups of control and KRN633-treated mothers. These results suggest that a critical period for determining retinal vascular patterning is present at the earliest stages of retinal vascular development, and that the impaired vascular endothelial growth factor signaling during this period induces abnormal architecture in the retinal vascular network.

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KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth

Cited by 59 publications

References 36 publications

Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound

Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound

KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Intrauterine Growth Restriction in Mice

Treatment of Mid‐Pregnant Mice with KRN633, an Inhibitor of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase, Induces Abnormal Retinal Vascular Patterning in Their Newborn Pups

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