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Potent Inhibition of Necroptosis by Simultaneously Targeting Multiple Effectors of the Pathway.
Pierotti, Catia L; Tanzer, Maria C; Jacobsen, Annette V; Hildebrand, Joanne M; Garnier, Jean-Marc; Sharma, Pooja; Lucet, Isabelle S; Cowan, Angus D; Kersten, Wilhelmus J A; Luo, Meng-Xiao; Liang, Lung-Yu; Fitzgibbon, Cheree; Garnish, Sarah E; Hempel, Anne; Nachbur, Ueli; Huang, David C S; Czabotar, Peter E; Silke, John; van Delft, Mark F; Murphy, James M; Lessene, Guillaume.
Afiliación
  • Pierotti CL; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Tanzer MC; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Jacobsen AV; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Hildebrand JM; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Garnier JM; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Sharma P; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Lucet IS; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Cowan AD; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Kersten WJA; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Luo MX; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Liang LY; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Fitzgibbon C; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Garnish SE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Hempel A; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Nachbur U; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Huang DCS; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Czabotar PE; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Silke J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • van Delft MF; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Murphy JM; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • Lessene G; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
ACS Chem Biol ; 15(10): 2702-2713, 2020 10 16.
Article en En | MEDLINE | ID: mdl-32902249
ABSTRACT
Necroptosis is an inflammatory form of programmed cell death that has been implicated in various human diseases. Compound 2 is a more potent analogue of the published compound 1 and inhibits necroptosis in human and murine cells at nanomolar concentrations. Several target engagement strategies were employed, including cellular thermal shift assays (CETSA) and diazirine-mediated photoaffinity labeling via a bifunctional photoaffinity probe derived from compound 2. These target engagement studies demonstrate that compound 2 binds to all three necroptotic effector proteins (mixed lineage kinase domain-like protein (MLKL), receptor-interacting serine/threonine protein kinase 1 (RIPK1) and receptor-interacting serine/threonine protein kinase 3 (RIPK3)) at different levels in vitro and in cells. Compound 2 also shows efficacy in vivo in a murine model of systemic inflammatory response syndrome (SIRS).
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Compuestos de Fenilurea / Sulfonamidas / Transducción de Señal / Inhibidores de Proteínas Quinasas / Necroptosis Límite: Animals / Female / Humans Idioma: En Revista: ACS Chem Biol Año: 2020 Tipo del documento: Article País de afiliación: Australia
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Compuestos de Fenilurea / Sulfonamidas / Transducción de Señal / Inhibidores de Proteínas Quinasas / Necroptosis Límite: Animals / Female / Humans Idioma: En Revista: ACS Chem Biol Año: 2020 Tipo del documento: Article País de afiliación: Australia