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ES2521676T3 - Nuevos agentes inhibidores de la proliferación y de la activación de transductores de señales y activadores de la transcripción (STATS) - Google Patents

Nuevos agentes inhibidores de la proliferación y de la activación de transductores de señales y activadores de la transcripción (STATS) Download PDF

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ES2521676T3
ES2521676T3 ES09794969.7T ES09794969T ES2521676T3 ES 2521676 T3 ES2521676 T3 ES 2521676T3 ES 09794969 T ES09794969 T ES 09794969T ES 2521676 T3 ES2521676 T3 ES 2521676T3
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stat3
stats
signal transducers
proliferation inhibitor
transcription activators
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Waldemar Priebe
Stanislaw Skora
Timothy Madden
Izabela Fokt
Charles Conrad
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

Un compuesto que tiene una fórmula estructural seleccionada entre el conjunto que consiste en:**Fórmula**

Description

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E09794969
28-10-2014
Tabla 1 Activación de los STATs en cánceres humanos
Tipo de tumor
STAT activado
Tumores de la sangre
Mieloma múltiple
STAT1 , STAT3
Leucemias: Dependientes del HTLV-1 Eritroleucemia Leucemia mielógena aguda (AML) Leucemia mielógena crónica (CML) Leucemia linfocítica granular grande (LGL)
STAT3, STAT5 STAT1, STAT5 STAT1 , STAT3, STAT5 STAT5 STAT3
Linfomas: Relacionado con el EBV/ de Burkitt Micosis fungoide Linfoma de células T cutáneas Linfoma no de Hodgkins (NHL) Linfoma anaplásico de células grandes (ALCL)
STAT3 STAT3 STAT3 STAT3 STAT3
Tumores sólidos
Cáncer de mama
STAT1 , STAT3, STAT5
Cáncer de cabeza y cuello
STAT1 , STAT3, STAT5
Melanoma
STAT3
Cáncer de ovario
STAT3
Cáncer de pulmones
STAT3
Cáncer pancreático
STAT3
Cáncer de próstata
STAT3
Glioma
STAT3, STAT5
Basándose en las referencias citadas en las REFS 12, 17, EBV, virus de Epstein-Barr; HTLV-1, virus linfotrópico T humano-1.
La familia de proteínas STAT (acrónimo de "signal transducer y activator of transcription" ) incluye unos factores de transcripción que son activados específicamente para regular la transcripción de un gen cuando las células se encuentran con citocinas y con factores de crecimiento. En los mamíferos, hay siete miembros conocidos de la familia de proteínas STAT: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b y STAT6. Yu, H., Jove, R., The STATS of Cancer -New Molecular Targets Come of Age [Los STATS de cáncer – Unas nuevas dianas moleculares alcanzan la madurez de edad], Nature Reviews, 4:97-105 (2004). Estas siete proteínas varían en cuanto a su tamaño entre 750 y 850 aminoácidos. Las proteínas STAT5a y STAT5b, citadas colectivamente en el presente texto como “STAT5”, están íntimamente relacionadas pero son codificadas por diferentes genes. Yu, H., Jove, R, The STATS of Cancer -New Molecular Targets Come of Age, Nature Reviews, 4:97-105 (2004)
Las proteínas STAT actúan como transductores de señales en el citoplasma y como activadores de la transcripción en el núcleo. Kisseleva T., Bhattacharya S., Braunstein J., Schindler C.W., Signaling Through the JAK/STAT Pathway, Recent Advances and Future Challenges [Señalización a través de la ruta de JAK/STAT, recientes avances y futuros retos], Gene 285: 1-24 (2002). Por ejemplo las proteínas STAT transducen a señales procedentes de receptores de citocinas, receptores de factores de crecimiento y tirosina cinasas citoplasmáticas, no de receptores, tales como Src y Abl en el núcleo de una célula, en donde ellas fijan al ADN y regulan la transcripción de un surtido de genes. Id. Como resultado de esto, las proteínas STAT regulan unas funciones fisiológicas, tales como una respuesta inmunitaria, una inflamación, una proliferación, una diferenciación, una supervivencia, una metástasis, una apoptosis y una tolerancia inmunitaria (p.ej. evasión desde el sistema inmunitario de tumores). Xie, T. y colaboradores, Stat3 Activation Regulates the Expression of Matrix Metalloproteinase-2 and Tumor Invasion and Metastasis [La activación de los Stat3 regula la expresión de la metaloproteinasa de matriz -2 y la invasión y metástasis de tumores], Oncogene 23: 3550-3560 (2004); Levy, D.E., Inghirami, G., STAT3: A Multifaceted Oncogene [ STAT3, un oncogén de múltiples facetas] , PNAS 103: 10151-5251-52 (2006).
Los STATs comparten unos dominios conservados estructural y funcionalmente, que incluyen: un dominio terminal de N que refuerza las interacciones entre dímeros de STAT en unos sitios de fijación de ADN adyacentes; un dominio de STAT con una hélice superenrollada, que está implicado en interacciones de una proteína con otra proteína; un dominio de fijación de ADN con un pliegue similar al de la inmunoglobulina para la proteína supresora de tumores p53; un dominio de engarzador similar al de la mano EF, que conecta a los dominios de fijación de ADN y de SH2; un dominio de SH2 que actúa como un conmutador dependiente de la fosforilación para controlar el reconocimiento de receptores y la fijación de ADN; y un dominio de transactivación terminal de C. Chen X., Vinkemeier U., Zhao Y., Jeruzalmi D., Darnell J.E., Kuriyan J., Crystal Structure of a Tyrosine Phosphorylated STAT1 Dimer Bound to DNA [Estructura cristalina de un dímero de STAT-1 fosforilado en tirosina, que está fijado a un ADN] , Cell 93: 827-839 (1998). Con el fin de fijarse a un ADN, las proteínas STAT deben de dimerizarse. Yu, H., Jove, R, The STATS of Cancer -New Molecular Targets Come of Age, Nature Reviews, 4:97105 (2004), Darnell, J.
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Claims (1)

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ES09794969.7T 2008-07-08 2009-06-26 Nuevos agentes inhibidores de la proliferación y de la activación de transductores de señales y activadores de la transcripción (STATS) Active ES2521676T3 (es)

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PCT/US2009/048782 WO2010005807A2 (en) 2008-07-08 2009-06-26 Novel inhibitors of proliferation and activation of signal transducer and activator of transcription (stats)

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