The recent success of imatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia has made tyrosine and serine/threonine kinases as major targets for cancer therapy. Currently, since only a small fraction of the human kinome has been targeted by reasonably selective and potent inhibitors, there is an urgent need to develop strategies for efficient discovery and optimization of new inhibitors. Towards this goal, we have recently developed a compound library of candidate ATP-competitive kinase inhibitors. We screened our collection of novel small molecules (approximately 2,000) against a panel of 16 cultured tumor cell lines for the ability to induce cell death. This search revealed one compound, ON 1231320, with remarkable cytotoxicity against the entire panel of 16 tumor cell lines. Kinase inhibition assays against a panel of 285 kinases revealed that this compound had a remarkable specificity towards Polo-like kinase 2 (Plk2 or Snk), a kinase involved in centrosome duplication and mitotic progression. As expected, tumor cells treated with ON 1231320 arrest in mitosis due to abnormal microtubule spindle development. Plk2 has recently been implicated as one of the kinases that links cellular metabolism to the cell cycle. Mitochondrial dysfunction, with resulting increased dependence on glycolysis, is frequently observed in cancer cells (known as the Warburg effect). Identification of pathways that promote cell survival under conditions of mitochondrial dysfunction has therapeutic implications. In a recent study, it has been shown that targeted ablation of the SCO2 gene in HCT116 human colon cancer cell line results in the ablation of mitochondrial respiration and that PLK2 is the most highly expressed gene in SCO2-/-cells. Furthermore, even a modest reduction in Plk2 levels in human cancer cells with defects in mitochondrial respiration results in the elimination of their ability to form xenografts in mice. In this proposal, we plan to further examine this potent and selective Plk2 inhibitor in order to determine important chemical characteristics and biological activity necessary for advanced pre-clinical development. We propose to study the effects of this compound on tumor growth in vitro and in vivo to determine how ON 1231320 will serve as a novel cancer chemotherapeutic.
The aims of this proposal are to: (1) Prepare an optimal formulation of ON 1231320 for stability and parenteral delivery;(2) Characterize the pharmacokinetic and pharmacodynamic properties of ON 1231320 in non-tumor and tumor-bearing mice;and (3) Evaluate anti-tumor efficacy of ON 01231320, determine the degree of inhibition of Plk2 required for inhibition of human tumor growth in xenograft models, and assess how ON 1231320 doses and schedules are related to the anti-tumor activity of the compound.
This application describes the discovery of a novel cancer therapeutic, ON 1231320, which could find a wide application in the treatment of some of the most difficult-to-treat cancers that are traditionally resistant to chemotherapy. ON 1231320 has a unique and targeted anti-cancer mechanism of action. In this application, we propose to develop optimal formulation, preclinical pharmacology, and anti-cancer efficacy profiles for ON 1231320 in preparation for a Phase I study in cancer patients.
