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 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.
Gumireddy
Kiranmai
K
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, Pennsylvania 19140, USA.
Reddy
M V Ramana
MV
Cosenza
Stephen C
SC
Boominathan
R
R
Boomi Nathan
R
R
Baker
Stacey J
SJ
Papathi
Nabisa
N
Jiang
Jiandong
J
Holland
James
J
Reddy
E Premkumar
EP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D000097869:Polo-Like Kinase 1
D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1