Your browser doesn't support javascript.
loading
BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells.
Campbell, Amy E; Oliva, Jonathan; Yates, Matthew P; Zhong, Jun Wen; Shadle, Sean C; Snider, Lauren; Singh, Nikita; Tai, Shannon; Hiramuki, Yosuke; Tawil, Rabi; van der Maarel, Silvère M; Tapscott, Stephen J; Sverdrup, Francis M.
Afiliación
  • Campbell AE; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Oliva J; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA.
  • Yates MP; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA.
  • Zhong JW; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Shadle SC; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Snider L; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, 98105, USA.
  • Singh N; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • Tai S; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA.
  • Hiramuki Y; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA.
  • Tawil R; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • van der Maarel SM; Department of Neurology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Tapscott SJ; Department of Human Genetics, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
  • Sverdrup FM; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. stapscot@fredhutch.org.
Skelet Muscle ; 7(1): 16, 2017 09 04.
Article en En | MEDLINE | ID: mdl-28870238
BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. METHODS: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures. RESULTS: Our screens identified several classes of molecules that include inhibitors of the bromodomain and extra-terminal (BET) family of proteins and agonists of the beta-2 adrenergic receptor. Further studies showed that compounds from these two classes suppress the expression of DUX4 messenger RNA (mRNA) by blocking the activity of bromodomain-containing protein 4 (BRD4) or by increasing cyclic adenosine monophosphate (cAMP) levels, respectively. CONCLUSIONS: These data uncover pathways involved in the regulation of DUX4 expression in somatic cells, provide potential candidate classes of compounds for FSHD therapeutic development, and create an important opportunity for mechanistic studies that may uncover additional therapeutic targets.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Proteínas de Homeodominio / Distrofia Muscular Facioescapulohumeral / Bibliotecas de Moléculas Pequeñas / Agonistas de Receptores Adrenérgicos beta 2 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Skelet Muscle Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Proteínas Nucleares / Proteínas de Homeodominio / Distrofia Muscular Facioescapulohumeral / Bibliotecas de Moléculas Pequeñas / Agonistas de Receptores Adrenérgicos beta 2 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Skelet Muscle Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido