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Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055.
Michino, Mayako; Khan, Tanweer A; Miller, Michael W; Fukase, Yoshiyuki; Vendome, Jeremie; Adura, Carolina; Glickman, J Fraser; Liu, Yiman; Wan, Liling; Allis, C David; Stamford, Andrew W; Meinke, Peter T; Renzetti, Louis M; Kargman, Stacia; Liverton, Nigel J; Huggins, David J.
Afiliación
  • Michino M; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Khan TA; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Miller MW; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Fukase Y; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Vendome J; Schrödinger, Inc., 1540 Broadway, 24th Floor, New York, New York 10036, United States.
  • Adura C; Fisher Drug Discovery Resource Center, The Rockefeller University, New York, New York 10065, United States.
  • Glickman JF; Fisher Drug Discovery Resource Center, The Rockefeller University, New York, New York 10065, United States.
  • Liu Y; Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
  • Wan L; Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.
  • Allis CD; Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York 10065, United States.
  • Stamford AW; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Meinke PT; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Renzetti LM; Department of Pharmacology, Weill Cornell Medicine, New York, New York 10021, United States.
  • Kargman S; Bridge Medicines, The Rockefeller University, 1230 York Avenue, Smith Hall Annex, C-Floor, New York, New York 10065, United States.
  • Liverton NJ; Sanders Tri-Institutional Therapeutics Discovery Institute, 1230 York Ave, Box 122, New York, New York 10065, United States.
  • Huggins DJ; Bridge Medicines, The Rockefeller University, 1230 York Avenue, Smith Hall Annex, C-Floor, New York, New York 10065, United States.
ACS Med Chem Lett ; 15(4): 524-532, 2024 Apr 11.
Article en En | MEDLINE | ID: mdl-38628784
ABSTRACT
Eleven-nineteen leukemia (ENL) is an epigenetic reader protein that drives oncogenic transcriptional programs in acute myeloid leukemia (AML). AML is one of the deadliest hematopoietic malignancies, with an overall 5-year survival rate of 27%. The epigenetic reader activity of ENL is mediated by its YEATS domain that binds to acetyl and crotonyl marks on histone tails and colocalizes with promoters of actively transcribed genes that are essential for leukemia. Prior to the discovery of TDI-11055, existing inhibitors of ENL YEATS showed in vitro potency, but had not shown efficacy in in vivo animal models. During the course of the medicinal chemistry campaign described here, we identified ENL YEATS inhibitor TDI-11055 that has an improved pharmacokinetic profile and is appropriate for in vivo evaluation of the ENL YEATS inhibition mechanism in AML.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos