RESUMO
Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Adenina/isolamento & purificação , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Mitose/efeitos dos fármacos , Mitose/fisiologia , Modelos Biológicos , Peso Molecular , Morfolinas/isolamento & purificação , Neoplasias/patologia , Inibidores de Proteínas Quinases/isolamento & purificação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The first tubulin targeting agents were approved as cancer chemotherapeutics over 40 years ago and tubulin as an antitumor target continues to attract significant drug discovery and development attention. Mechanism of action as defined by tubulin binding sites and effect on microtubules distinguishes these agents, but the end result is equivalent in that microtubule disruption leads to cell cycle arrest at G2/M phase of the cell cycle and subsequent apoptotic cell death. OBJECTIVES: The goal of this review is to describe the state of clinical development of tubulin targeting agents as of early 2008, with descriptions of clinical experience slanted toward the most advanced trials for each agent. METHOD: Objective information in this review was obtained exclusively from public sources that included journals, scientific meeting abstracts, posters and oral presentations, websites and public presentations from companies. Opinions expressed in this review are exclusively from the author. RESULTS/CONCLUSIONS: A large number of tubulin targeting agents are currently in clinical development, including microtubule stabilizing and destabilizing compounds acting through all three of the characterized tubulin binding sites. With the approval of ixabepilone for refractory breast cancer, the epothilones appear best positioned to make an impact among the new microtubule stabilizing compounds. There are 17 microtubule destabilizing agents under clinical assessment, with many only in Phase I and results to date include at best modest efficacy signals with no obvious indication trend.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Desenho de Fármacos , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/patologia , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Moduladores de Tubulina/químicaRESUMO
A novel series of 4-arylaminoquinazolines were identified from a cell-based screening assay as potent apoptosis inducers. Through structure-activity relationship studies, MPC-6827 and its close structural analogue, MPI-0441138, were discovered as proapoptotic molecules and mitotic inhibitors with potencies at low nanomolar concentrations in multiple tumor cell lines. Photoaffinity and radiolabeled analogues of MPC-6827 were found to bind a 55-kDa protein, and this binding was competed by MPC-6827, paclitaxel, and colchicine, but not vinblastine. MPC-6827 effectively inhibited the polymerization of tubulin in vitro, competed with colchicine binding, and disrupted the formation of microtubules in a variety of tumor cell lines, which together showed the molecular target as tubulin. Treatment of MCF-7 breast carcinoma or Jurkat leukemia cells with MPC-6827 led to pronounced G2-M cell cycle arrest followed by apoptosis. Apoptosis, as determined by terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling assay, was preceded by loss of mitochondrial membrane potential, cytochrome c translocation from mitochondria to nuclei, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase. MPC-6827 was equipotent in an in vitro growth inhibition assay in several cancer cell lines regardless of the expression levels of the multidrug resistance ABC transporters MDR-1 (Pgp-1), MRP-1, and BCRP-1. In B16-F1 allografts and in OVCAR-3, MIAPaCa-2, MCF-7, HT-29, MDA-MB-435, and MX-1 xenografts, statistically significant tumor growth inhibition was observed with MPC-6827. These studies show that MPC-6827 is a microtubule-disrupting agent with potent and broad-spectrum in vitro and in vivo cytotoxic activities and, therefore, MPC-6827 is a promising candidate for development as a novel therapeutic for multiple cancer types.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/fisiologia , Quinazolinas/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Caspases/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Marcação In Situ das Extremidades Cortadas , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Nus , Quinazolinas/síntese química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Targeting cellular proliferation persists as a mainstay of cancer therapeutic strategy. Although microtubule-targeting drugs (such as taxanes and vinca alkaloids) have been used successfully in the clinic to treat a variety of cancers, they carry substantial liabilities that have spurred drug companies to aggressively pursue new tubulin-targeting drug candidates with improved efficacy and toxicity profiles. The recent discoveries of new mitotic targets for cancer therapy (such as kinesin spindle protein, Aurora kinases and Polo-like kinase-1) have also stimulated intense work focused on identifying novel antimitotic drugs directed at these new targets. A number of novel antimitotic drugs have demonstrated encouraging activity in preclinical models and have progressed into clinical development. This review focuses on selected new antimitotic drugs under evaluation in clinical trials.