This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-0945v1 69/17/6969    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gilmartin, A. G. Articles by Laquerre, S. G. PubMed PubMed Citation Articles by Gilmartin, A. G. Articles by Laquerre, S. G.

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania

Requests for reprints: Aidan G. Gilmartin, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426. Phone: 610-917-4078; Fax: 610-917-4181; E-mail: Aidan.G.Gilmartin{at}GSK.com.

Key Words: GSK461364A • Plk1

Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G₂ and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. We have identified a potent, selective, reversible, ATP-competitive inhibitor of Plk1, GSK461364A, capable of inhibiting cell growth of most proliferating cancer cell lines tested. We observe distinct cell cycle effects of GSK461364A depending on the dose used. The predominant phenotype for cells treated with GSK461364A is prometaphase arrest with characteristic collapsed polar polo spindle. At high concentrations, GSK461364A delays mitotic entry in G₂ followed by gradual progression into terminal mitosis; in some cell lines, this correlates with decreased apoptosis. Cell culture growth inhibition by GSK461364A can be cytostatic or cytotoxic but leads to tumor regression in xenograft tumor models under proper dose scheduling. Finally, we describe pharmacodynamic biomarkers of GSK461364A activity (pHH3 and Plk1) that are currently being evaluated in human cancer clinical trials. [Cancer Res 2009;69(17):6969–77]