Abstract
AZD0530, an orally available Src inhibitor, demonstrated potent antimigratory and anti-invasive effects in vitro, and inhibited metastasis in a murine model of bladder cancer. Antiproliferative activity of AZD0530 in vitro varied between cell lines (IC(50) 0.2 ->10μM). AZD0530 inhibited tumor growth in 4/10 xenograft models tested and dynamically inhibited in vivo phosphorylation of Src substrates paxillin and FAK in both growth-inhibition-resistant and -sensitive xenografts. The activity of AZD0530 in NBT-II bladder cancer cells in vitro was consistent with inhibition of cell migration and stabilization of cell-cell adhesion. These data suggest a dominant anti-invasive pharmacology for AZD0530 that may limit tumor progression in a range of cancers. AZD0530 is currently in Phase II clinical trials.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / pharmacology*
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Benzodioxoles / pharmacology*
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Clinical Trials, Phase II as Topic
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Focal Adhesion Kinase 1 / metabolism
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Humans
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Mice
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Mice, Nude
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NIH 3T3 Cells
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Neoplasm Invasiveness
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Paxillin / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Quinazolines / pharmacology*
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Rats
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Rats, Nude
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Transplantation, Heterologous
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Urinary Bladder Neoplasms / drug therapy*
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Urinary Bladder Neoplasms / enzymology
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Urinary Bladder Neoplasms / pathology
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Xenograft Model Antitumor Assays*
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src-Family Kinases / antagonists & inhibitors*
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src-Family Kinases / metabolism
Substances
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Antineoplastic Agents
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Benzodioxoles
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Neoplasm Proteins
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PXN protein, human
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Paxillin
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Protein Kinase Inhibitors
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Quinazolines
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saracatinib
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Focal Adhesion Kinase 1
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PTK2 protein, human
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src-Family Kinases