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Nat Commun ; 6: 7227, 2015 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-26085373


Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

Quinasa de la Caseína II/antagonistas & inhibidores , Senescencia Celular/efectos de los fármacos , Terapia Molecular Dirigida , Naftiridinas/uso terapéutico , Fosfohidrolasa PTEN/deficiencia , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Quinasa de la Caseína II/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Células HCT116 , Humanos , Masculino , Ratones Transgénicos , Naftiridinas/farmacología , Proteínas Nucleares/metabolismo , Fenazinas , Proteína de la Leucemia Promielocítica , ARN Interferente Pequeño , Factor de Transcripción STAT3/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo
Nat Chem Biol ; 11(5): 347-354, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25848931


Huntington's disease (HD) is a currently incurable neurodegenerative condition caused by an abnormally expanded polyglutamine tract in huntingtin (HTT). We identified new modifiers of mutant HTT toxicity by performing a large-scale 'druggable genome' siRNA screen in human cultured cells, followed by hit validation in Drosophila. We focused on glutaminyl cyclase (QPCT), which had one of the strongest effects on mutant HTT-induced toxicity and aggregation in the cell-based siRNA screen and also rescued these phenotypes in Drosophila. We found that QPCT inhibition induced the levels of the molecular chaperone αB-crystallin and reduced the aggregation of diverse proteins. We generated new QPCT inhibitors using in silico methods followed by in vitro screening, which rescued the HD-related phenotypes in cell, Drosophila and zebrafish HD models. Our data reveal a new HD druggable target affecting mutant HTT aggregation and provide proof of principle for a discovery pipeline from druggable genome screen to drug development.

Aminoaciltransferasas/efectos de los fármacos , Aminoaciltransferasas/genética , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/genética , ARN Interferente Pequeño , Aminoaciltransferasas/antagonistas & inhibidores , Animales , Células Cultivadas , Biología Computacional , Drosophila , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Proteína Huntingtina , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Pez Cebra , Cadena B de alfa-Cristalina/metabolismo
Expert Opin Ther Targets ; 13(5): 551-67, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19368497


BACKGROUND: Alzheimer's disease (AD), the most common form of degenerative dementia, represents a tremendous unmet medical need. Although AD had already been described about 100 years ago and despite enormous research efforts, at present only few symptomatic treatment options exist for the more than 25 million patients worldwide. This situation might change as many targets for therapeutic intervention have been identified based on the in-depth study of the pathology of the disease in model systems and humans, and of its underlying genetics. OBJECTIVE/METHODS: These targets are highlighted in the context of contemporary drug discovery for the identification of new therapies. RESULTS/CONCLUSIONS: 'Translation' of recent discoveries into disease-modifying therapies has not yet been accomplished. The future will show whether the current drug discovery and development 'pipelines' of pharmaceutical companies yield efficacious new medicines for AD.

Enfermedad de Alzheimer/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Nootrópicos/uso terapéutico , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/inmunología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fibras Colinérgicas/efectos de los fármacos , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Inmunización Pasiva , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Ovillos Neurofibrilares/efectos de los fármacos , Nootrópicos/farmacología , Placa Amiloide/efectos de los fármacos , Vacunación