Polo-like kinases (PLKs) have numerous roles in both mitosis and meiosis, including functions related to chromosome segregation, cohesin removal, and kinetochore orientation. PLKs require specific regulation during meiosis to control those processes. There are five mammalian Polo kinases, Polo-like kinase (Plk) 1-5 which share two 30 amino acid conserved motifs, termed polo boxes, as well as additional residues in the kinase domain. PLK2 is a p53 target gene. PLK2 plays an important role in cell cycle control through the specific phosphorylation of centrosome-associated substrates. Specifically, PLK-2 regulates centriole duplication that occurs at the G1/S border. It is coordinately regulated by CDK2/cyclin E and CDK2/cyclin A complexes, as well as PLK4. In summary, ON1231320 is a selective inhibitor of PLK2 and blocks tumor cell cycle progression in mitosis, causing apoptotic cell death. ON1231320 synergizes with Paclitaxel, and is efficacious in inhibiting tumor growth in vivo.
ON1231320 has no inhibitory activity against PLK1, PLK3 and PLK4 (all IC50>10 µM). It does not appreciably inhibit tubulin polymerization. ON1231320 activates programmed cell death in human tumor cells. ON1231320 also inhibits cell proliferation in 16 tumor cell lines (IC50= 0.035-0.2 µM). They include DU145, MCF-7, BT474, SK-OV-3, MIA-PaCa-2, SK-MEL-28, A549, U87, COLO-205, HELA, H1975, RAJI, U205, K562, and GRANTA-519 cells. ON1231320 does not affect normal human fibroblasts. ON1231320 results in significant inhibition of tumor growth. Furthermore, ON1231320 is well tolerated in mice, and reduces tumor burden in mice carrying subcutaneous and orthotopic xenografts of human tumor cells.
In summary, ON1231320, an arylsulfonyl pyrido-pyrimidinone, specifically inhibits PLK2 isoform (SNK). ON1231320 also causes mitotic catastrophe and apoptosis of cultured tumor cell lines.