YM-201627: An orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation

Amino, Nobuaki; Ideyama, Yukitaka; Yamano, Michiyo; Kuromitsu, Sadao; Tajinda, Katsunori; Samizu, Kiyohiro; Matsuhisa, Akira; Kudoh, Masafumi; Shibasaki, Masayuki

doi:10.1016/j.canlet.2005.06.037

Cited by 51 publications

(52 citation statements)

References 22 publications

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“…Finally, given the established role of VEGF and basic fibroblast growth factor (bFGF) in melanoma angiogenesis (30)(31)(32), we evaluated VEGF and bFGF expression in brain metastatic tumors. Consistent with the microvessel density findings, VEGF and bFGF staining was prominent in the brain metastatic lesions, but not in lesions formed by SOCS-1-transfected cells ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis

Huang¹,

Steeg

Price

et al. 2008

Cancer Research

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Our recent study found that activation of signal transducer and activator of transcription 3 (Stat3) is up-regulated in human brain metastatic cells and contributes to brain metastasis of melanoma. However, the molecular mechanisms underlying this increased Stat3 activation and effect on brain metastasis are unknown. In this report, we showed that the expression of Janus-activated kinase 2 (JAK2), a Stat3 activator, was increased, whereas the expression of a negative regulator of Stat3, suppressor of cytokine signaling-1 (SOCS-1), was reduced in the brain metastatic melanoma cell line A375Br, relative to that in the parental A375P cell line. Consistently, SOCS-1 expression was also lower in the human brain metastatic tissues than in the primary melanoma tissues. Mechanistically, increased JAK2 expression in the A375Br cells was due to, at least in part, its decreased degradation, which was directly correlated with low expression of SOCS-1. Moreover, restoration of SOCS-1 expression resulted in the inhibition of Stat3 activation, whereas depletion of SOCS-1 up-regulated Stat3 activation. These clinical, experimental, and mechanistic findings strongly suggest that increased activation of Stat3 in brain metastatic melanoma cells might be due to decreased SOCS-1 expression. Furthermore, restoration of SOCS-1 expression in brain metastatic A375Br cells significantly inhibited brain metastasis in animal models (P < 0.001). Additionally, alterations of SOCS-1 expression profoundly affected the expression of matrix metalloproteinase-2 (MMP-2), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) and the melanoma cell invasion and angiogenesis. Collectively, these data suggest that the loss of SOCS-1 expression is a critical event, leading to elevated Stat3 signaling and overexpression of MMP-2, bFGF, and VEGF, as well as enhanced invasion and angiogenesis of melanoma cells, consequently promoting brain metastasis. [Cancer Res 2008;68(23):9634-42]

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Section: Resultsmentioning

confidence: 99%

Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis

Huang¹,

Steeg

Price

et al. 2008

Cancer Research

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“…The oxime derivative YM-359445 (as the tartrate salt) (7), very recently reported by the same company, shows similar biologic behaviour, but is more active, showing an IC 50 of 8.5 nM in an HTRF assay. It inhibits autophosphorylation and sprout formation in vitro at 0.001 and 0.003 M concentration, respectively, and inhibits tumor growth (including human lung cancer A549 xenografts) in vivo at doses of 0.5 to 4 mg/kg [64].…”

Section: Indolin-2-onesmentioning

confidence: 99%

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Schenone¹,

Bondavalli²,

Botta

2007

CMC

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Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.

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“…In order to improve the maneuver of drug-receptor interaction research and existed drug screening strategy aiming at a specific receptor, some biological affinity chromatographic systems with better specification on methods have been developed [8]. The incorporation of isolated cytosolic proteins and enzymes into an affinity chromatography column and the application of the resulting column to the study of ligand-protein interactions were first demonstrated by Chaiken and Carr and have been extensively studied [9].…”

Section: Introductionmentioning

confidence: 99%

Preparation and Application of Modified VEGFR-2 Cell Membrane Chromatographic Separation System

et al. 2016

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YM-201627: An orally active antitumor agent with selective inhibition of vascular endothelial cell proliferation

Cited by 51 publications

References 22 publications

Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis

Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis

Antiangiogenic Agents: an Update on Small Molecule VEGFR Inhibitors

Preparation and Application of Modified VEGFR-2 Cell Membrane Chromatographic Separation System

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