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LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity.
Bonday, Zahid Q; Cortez, Guillermo S; Grogan, Michael J; Antonysamy, Stephen; Weichert, Ken; Bocchinfuso, Wayne P; Li, Fengling; Kennedy, Steven; Li, Binghui; Mader, Mary M; Arrowsmith, Cheryl H; Brown, Peter J; Eram, Mohammad S; Szewczyk, Magdalena M; Barsyte-Lovejoy, Dalia; Vedadi, Masoud; Guccione, Ernesto; Campbell, Robert M.
Afiliación
  • Bonday ZQ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Cortez GS; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Grogan MJ; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Antonysamy S; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Weichert K; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Bocchinfuso WP; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Li F; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Kennedy S; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Li B; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Mader MM; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
  • Arrowsmith CH; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Brown PJ; Department of Medical Biophysics, University of Toronto and Princess Margaret Cancer Centre, 101 College Street, MaRS South Tower, Suite 707, Toronto, ON M5G 1L7, Canada.
  • Eram MS; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Szewczyk MM; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Barsyte-Lovejoy D; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Vedadi M; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Guccione E; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • Campbell RM; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
ACS Med Chem Lett ; 9(7): 612-617, 2018 Jul 12.
Article en En | MEDLINE | ID: mdl-30034588
Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the formation of symmetric dimethylarginine in a number of nuclear and cytoplasmic proteins. Although the cellular functions of PRMT5 have not been fully unraveled, it has been implicated in a number of cellular processes like RNA processing, signal transduction, and transcriptional regulation. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma. Here, we describe the identification and characterization of a novel and selective PRMT5 inhibitor with potent in vitro and in vivo activity. Compound 1 (also called LLY-283) inhibited PRMT5 enzymatic activity in vitro and in cells with IC50 of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, compound 2 (also called LLY-284), was much less active. Compound 1 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells.

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos