Abstract
Elevated expression of polo-like kinase1 (Plk1) has been reported in many human tumors, and inhibition of Plk1 activity results in their mitotic arrest and apoptosis. Here we describe the profile of ON01910, a small molecule inhibitor of Plk1 activity, which induces mitotic arrest of tumor cells characterized by spindle abnormalities leading to their apoptosis. This compound was not ATP-competitive, but competed for the substrate binding site of the enzyme. In vivo, this compound did not exhibit hematotoxicity, liver damage, or neurotoxicity, and was a potent inhibitor of tumor growth in a variety of xenograft nude mouse models. ON01910 showed strong synergy with several chemotherapeutic agents, often inducing complete regression of tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity
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Apoptosis
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Cell Cycle / physiology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Female
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Humans
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Mice
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Mice, Nude
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Molecular Structure
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Neoplasms, Experimental / metabolism
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Polo-Like Kinase 1
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / toxicity
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Spindle Apparatus / drug effects*
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Spindle Apparatus / metabolism
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Adenosine Triphosphate
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Protein Kinases
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Protein Serine-Threonine Kinases