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Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.
Li, Jing; Yakushi, Tanya; Parlati, Francesco; Mackinnon, Andrew L; Perez, Christian; Ma, Yuyong; Carter, Kyle P; Colayco, Sharon; Magnuson, Gavin; Brown, Brock; Nguyen, Kevin; Vasile, Stefan; Suyama, Eigo; Smith, Layton H; Sergienko, Eduard; Pinkerton, Anthony B; Chung, Thomas D Y; Palmer, Amy E; Pass, Ian; Hess, Sonja; Cohen, Seth M; Deshaies, Raymond J.
Afiliación
  • Li J; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
  • Yakushi T; Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
  • Parlati F; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
  • Mackinnon AL; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
  • Perez C; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
  • Ma Y; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
  • Carter KP; Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
  • Colayco S; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Magnuson G; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Brown B; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Nguyen K; Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
  • Vasile S; Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
  • Suyama E; Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
  • Smith LH; Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute Lake Nona, Orlando, Florida, USA.
  • Sergienko E; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Pinkerton AB; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Chung TDY; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Palmer AE; Department of Chemistry and Biochemistry, University of Colorado Boulder, Boulder, Colorado, USA.
  • Pass I; Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
  • Hess S; Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
  • Cohen SM; Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
  • Deshaies RJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
Nat Chem Biol ; 13(5): 486-493, 2017 05.
Article en En | MEDLINE | ID: mdl-28244987
ABSTRACT
The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Quinolinas / Transactivadores / Inhibidores de Proteasoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2017 Tipo del documento: Article
Texto completo
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XML
PubMed Links
Buscar en Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Quinolinas / Transactivadores / Inhibidores de Proteasoma Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Año: 2017 Tipo del documento: Article