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.
Public Health Relevance: 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.
Thesaurus Terms: Atp-Protein Phosphotransferase;Ablation;Address;Affect;Antimitotic Agents;Antimitotic Drugs;Antimitotics;Apoptosis;Apoptosis Pathway;Area;Assay;Athymic Mice;Athymic Nude Mouse;Bioassay;Bioavailability;Biologic Assays;Biologic Availability;Biologic Characteristic;Biological;Biological Assay;Biological Availability;Biological Characteristics;Colo 205;Cancer Patient;Cancer Treatment;Cancers;Cell Cycle;Cell Death;Cell Division Cycle;Cell Growth In Number;Cell Multiplication;Cell Proliferation;Cell Survival;Cell Viability;Cells;Cellular Proliferation;Centrosome;Chemicals;Chronic Myelocytic Leukemia;Chronic Myelogenous Leukemia;Chronic Myeloid Leukemia;Chronic Myeloid Leukemia T(9;22) (Q34;Q11), Bcr/Abl Positive;Clinical;Clinical Research;Clinical Study;Clinical Trials;Collection;Colo-205;Colo205;Colon;Cultured Neoplastic Cells;Cultured Tumor Cells;Data;Defect;Dependence;Development;Disease;Disorder;Dose;Drug Formulations;Drug Kinetics;Drug Precursors;Drugs;Dysfunction;Ec 2.7;Formulation;Functional Disorder;Future;Generalized Growth;Generations;Genes;Gleevec;Glivec;Glycolysis;Goals;Growth;Hct 116 Cells;Hct116;Hct116 Cells;Hplc;Heterograft;Heterologous Transplantation;High Performance Liquid Chromatography;High Pressure Liquid Chromatography;High Speed Liquid Chromatography;Human;Hydrogen Oxide;Imatinib;In Vitro;Injectable;Intermediary Metabolism;Intravenous;Kinases;L-Tyrosine;L-Isomer Tyrosine;Loinc Axis 2 Property;Laboratories;Lead;Leukemia, Granulocytic, Chronic;Libraries;Link;Lytotoxicity;M Phase;M Phase (Cell Cycle);Malignant Cell;Malignant Neoplasm Therapy;Malignant Neoplasm Treatment;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Medication;Metabolic Processes;Metabolism;Method Loinc Axis 6;Methodology;Methods;Mice;Mice Mammals;Micro-Tubule;Microtubular Function Inhibitors;Microtubules;Mitochondria;Mitosis;Mitosis Inhibitor Agents;Mitosis Inhibitor Drugs;Mitosis Inhibitors;Mitosis Stage;Mitotic;Mitotic Inhibitor Agents;Mitotic Inhibitor Drugs;Mitotic Inhibitors;Modern Man;Molecular;Murine;Mus;Myelosuppression;Nude Mice;Oral;Pbmc;Plk Gene Product;Ptk Inhibitors;Pathway Interactions;Pb Element;Peripheral Blood Mononuclear Cell;Ph'chromosome Positive Chronic Myelocytic Leukemia;Ph'chromosome Positive Chronic Myelogenous Leukemia;Ph'chromosome Positive Chronic Myeloid Leukemia;Ph'positive Chronic Granulocytic Leukemia;Ph1 Chromosome Positive Chronic Myelocytic Leukemia;Ph1 Chromosome Positive Chronic Myelogenous Leukemia;Ph1 Chromosome Positive Chronic Myeloid Leukemia;Ph1 Positive Chronic Granulocytic Leukemia;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacodynamics;Pharmacokinetics;Pharmacology;Phase;Phase 2 Clinical Trials;Phase I Study;Phase Ii Clinical Trials;Philadelphia Chromosome Positive Cml;Philadelphia Chromosome Positive Chronic Granulocytic Leukemia;Philadelphia Chromosome Positive Chronic Myelocytic Leukemia;Philadelphia Chromosome Positive Chronic Myelogenous Leukemia;Philadelphia Chromosome Positive Chronic Myeloid Leukemia;Phosphates;Phosphorylation;Phosphotransferases;Physiologic Availability;Physiopathology;Plk1 Protein;Polo-Like Kinase;Preparation;Pro-Drugs;Prodrugs;Programmed Cell Death;Property;Protein Kinase;Protein Phosphorylation;Protein Tyrosine Kinase Inhibitors;Protein-Serine Kinase;Protein-Serine-Threonine Kinases;Protein-Threonine Kinase;Regimen;Research;Resistance;Respiration;Route;Stpk13 Gene Product;Schedule;Serine Kinase;Serine-Threonine Kinases;Sodium Chloride;Sodium Chloride (Nacl);Specificity;Tk Inhibitors;Therapeutic;Therapeutic Agents;Threonine Kinase;Tissue Growth;Transphosphorylases;Tumor Cell;Tumor Cell Line;Tyrosine;Tyrosine Kinase Inhibitor;Warburg Effect;Water;Work;Xenograft;Xenograft Model;Xenograft Procedure;Xenotransplantation;Anticancer Therapy;Base;Cancer Cell;Cancer Therapy;Chemical Property;Chemotherapy;Clinical Investigation;Colon Cancer Cell Line;Cytotoxicity;Design;Designing;Developmental;Disease/Disorder;Drug/Agent;Effective Therapy;Effective Treatment;Experiment;Experimental Research;Experimental Study;Glycogen Synthase A Kinase;Heavy Metal Pb;Heavy Metal Lead;Human Plk1 Protein;Human Subject;Hydroxyalkyl Protein Kinase;In Vivo;Inhibitor;Inhibitor/Antagonist;Inorganic Phosphate;Intraperitoneal;Kinase Inhibitor;Malignancy;Mitochondrial;Mitochondrial Dysfunction;Mouse Model;Necrocytosis;Neoplasm/Cancer;Neoplastic Cell;Novel;Ontogeny;Para-Tyrosine;Pathophysiology;Pathway;Pharmacodynamic Model;Phase 1 Study;Phase 2 Trial;Phase Ii Protocol;Phase Ii Trial;Phosphate Ester;Phosphorylase B Kinase Kinase;Physical Property;Polo-Like Kinase 1;Pre-Clinical;Pre-Clinical Study;Pre-Clinical Trial;Preclinical;Preclinical Study;Preclinical Trial;Research Study;Resistant;Respiratory Mechanism;Salt;Small Molecule;Success;Tumor;Tumor Growth
