Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors

Shimizu, Toshiyuki; Fujiwara, Yasunari; Osawa, Tatsushi; Sakai, Teruyuki; Kubo, Kin‐ya; Kubo, Kazuo; Nishitoba, Tsuyoshi; Kimura, Kaname; Senga, Terufumi; Murooka, Hideko; Iwai, Akemi; Fukushima, Kayoko; Yoshino, Toshihiko; Miwa, Atsushi

doi:10.1016/j.bmcl.2003.12.019

Cited by 23 publications

(16 citation statements)

References 13 publications

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“…We have previously reported that proliferation of DGC cells was stimulated by FGF-7, which is a ligand of FGFR-2, but not by VEGF. Ki23057 blocks the autophosphorylation of fibroblast growth factor receptor 2 and VEGFR-3 (Shimizu et al, 2004;Nakamura et al, 2006). Ki23057 might decrease the growth of DGC tumour by inhibiting the FGFR-2 signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Small-synthetic molecules that interrupt proliferation-related receptor tyrosine kinase (RTK) pathways, Ki23057 (Shimizu et al, 2004), was used in this study. Ki23057 was dissolved in distilled water, stored in a light-shielded container at 4 1C, and used within 5 days.…”

Section: Phosphorylation Inhibitormentioning

confidence: 99%

“…Beginning 7 days after tumour inoculation, medication was administered orally five times weekly for 2 weeks. As the elimination half-life (t 1/2 ) of Ki23057 is 93 h on oral administration (Shimizu et al, 2004), orally five times weekly administration of Ki23057 contribute to efficacy. The mice were killed 3 weeks after tumour inoculation; gastric tumour size and total number and weight of metastatic LNs in tumours resected from Ki23057-treated animals (25 mg kg À1 day À1 ; n ¼ 8) were compared with those in tumours resected from vehicle control animals (n ¼ 8).…”

Section: Animal Modelsmentioning

confidence: 99%

“…Ki23057, a newly developed tyrosine kinase inhibitor, competes with ATP for the binding site in the kinase and therefore blocks the autophosphorylation of VEGFR-3 and fibroblast growth factor receptor 2 (FGFR-2) (Shimizu et al, 2004;Nakamura et al, 2006). The characteristic clinical features of diffuse-type gastric carcinoma (DGC), a diffusely infiltrating type of gastric carcinoma also known as scirrhous gastric carcinoma, include a high frequency of metastasis to the LNs (Hippo et al, 2001;Nakazawa et al, 2003) and to the peritoneum (Yashiro et al, 1996;Takemura et al, 2004;Tendo et al, 2005).…”

mentioning

confidence: 99%

“…The characteristic clinical features of diffuse-type gastric carcinoma (DGC), a diffusely infiltrating type of gastric carcinoma also known as scirrhous gastric carcinoma, include a high frequency of metastasis to the LNs (Hippo et al, 2001;Nakazawa et al, 2003) and to the peritoneum (Yashiro et al, 1996;Takemura et al, 2004;Tendo et al, 2005). Although we currently reported the effects of Ki23057 on the peritoneal dissemination of DGC with an amplification of the activated FGF-R2 (K-samII) gene (Shimizu et al, 2004;Nakamura et al, 2006), no candidate agent as VEGFR-3 phosphorylation inhibitor has yet been proposed for the molecular target therapy of LN metastasis. The molecular controls of tumour-induced lymphangiogenesis through the VEGFR-3 signalling system may be targets for novel therapeutics designed to restrict LN metastasis.…”

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confidence: 99%

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Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

et al. 2009

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BACKGROUND: Vascular endothelial growth factor receptor-3 (VEGFR-3) signalling mediates lymphangiogenesis and lymphatic invasion; however, the effect of VEGFR-3 inhibition on the lymph node (LN) metastasis remains unclear. The aim of this study is to clarify the benefit of a VEGFR-3 inhibitor Ki23057 for LN metastasis. METHODS: Ki23057 was administered orally to gastric cancer models created by orthotopic inoculation of diffuse-type gastric cancer cells, OCUM-2MLN. The effects of Ki23057 on lymphatic vessel invasion, lymphatic vessel density, and VEGFR-3 phosphorylation were examined by immunostaining or immunoblotting. RESULTS: Ki23057 inhibited the autophosphorylation of VEGFR-3, with IC 50 values of 4.3 nM in the cell-free kinase assay. Murine gastric cancer models created by the orthotopic inoculation of OCUM-2MLN cells showed the diffusely infiltrating growth and frequently developed LN metastasis. The oral administration of Ki23057 significantly (Po0.01) reduced the size of orthotopic tumours and the number of the metastatic LN in gastric cancer models. The degree of lymphatic invasion and lymphangiogenesis was significantly (Po0.05) lower in the gastric tumours treated by Ki23057. Ki23057 inhibited the phosphorylation of VEGFR-3 of lymphatic endothelial cells in gastric tumours. CONCLUSION: The inhibition of lymphangiogenesis targeting VEGFR-3 phosphorylation is a therapeutic strategy for inhibiting LN metastasis of diffuse-type gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Inhibitormentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

et al. 2009

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Bis‐aroylhydrazone based on 2,2′‐bis substituted diphenylamine for synthesis of new binuclear organotin (IV) complexes: Spectroscopic characterization, crystal structures, in vitro DNA‐binding, plasmid DNA cleavage, PCR and cytotoxicity against MCF7 cell line

Yousefi

Sedaghat

Shafiei

2019

Applied Organom Chemis

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have been synthesized from reaction of R 2 SnCl 2 (R = Me, Ph and Bu) with a 2,2′-bis-substituted diphenylamine arοylidene hydrazone, H 4 L. The synthesized compounds were investigated by elemental analysis and infrared, 1 H-NMR and 119 Sn-NMR spectroscopy. The structures of H 4 L, Me 4 Sn 2 L and Bu 4 Sn 2 L were also confirmed by X-ray crystallography. H 4 L molecules adopt (E)-configuration and keto-tautomeric form in the solid state. In all complexes, the bis-hydrazone acts as a tetra-anionic ligand with two contiguous ONO tridentate domains that coordinate the two R 2 Sn moieties in the enolate form.The coordination environments of both tin centers are five-coordinate. DNAbinding studies were performed by UV-Vis spectroscopy, and the results indicate that the synthesized compounds significantly interact with calf thymus-DNA in the intercalative mode. The results of polymerase chain reaction assay show that all the compounds affect on amplification of DNA, and complexes are more effective than ligands. The in vitro cytotoxicity against the human breast cancer line (MCF7) was determined using the MTT assay, and H 4 L and the dibutytin complex showed higher activity.

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