ON01910, a non-ATP-competitive small molecule inhibitor of Plk1, is a potent anticancer agent

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 cha...

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Bibliographic Details
Published in:Cancer cell 2005-03, Vol.7 (3), p.275-286
Main Authors: Gumireddy, Kiranmai, Reddy, M.V. Ramana, Cosenza, Stephen C., Nathan, R. Boomi, Baker, Stacey J., Papathi, Nabisa, Jiang, Jiandong, Holland, James, Reddy, E. Premkumar
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Apoptosis
Cell Cycle - physiology
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Dose-Response Relationship, Drug
Female
Humans
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental - metabolism
Polo-Like Kinase 1
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - toxicity
Protein Kinases - genetics
Protein Kinases - metabolism
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Spindle Apparatus - drug effects
Spindle Apparatus - metabolism
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2005.02.009