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Discovery of PFI-6, a small-molecule chemical probe for the YEATS domain of MLLT1 and MLLT3.
Raux, Brigitt; Buchan, Karly A; Bennett, James; Christott, Thomas; Dowling, Matthew S; Farnie, Gillian; Fedorov, Oleg; Gamble, Vicki; Gileadi, Carina; Giroud, Charline; Huber, Kilian V M; Korczynska, Magdalena; Limberakis, Chris; Narayanan, Arjun; Owen, Dafydd R; Sáez, Laura Díaz; Stock, Ingrid A; Londregan, Allyn T.
Afiliación
  • Raux B; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Buchan KA; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Bennett J; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Christott T; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Dowling MS; Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
  • Farnie G; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Fedorov O; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Gamble V; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Gileadi C; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Giroud C; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Huber KVM; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Korczynska M; Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
  • Limberakis C; Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
  • Narayanan A; Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
  • Owen DR; Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA.
  • Sáez LD; Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK; Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • Stock IA; Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
  • Londregan AT; Pfizer Worldwide Research and Development, Cambridge, MA 02139, USA. Electronic address: allyn.t.londregan@pfizer.com.
Bioorg Med Chem Lett ; 98: 129546, 2024 Jan 15.
Article en En | MEDLINE | ID: mdl-37944866
ABSTRACT
Epigenetic proteins containing YEATS domains (YD) are an emerging target class in drug discovery. Described herein are the discovery and characterization efforts associated with PFI-6, a new chemical probe for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). For hit identification, fragment-like mimetics of endogenous YD ligands (crotonylated histone-containing proteins), were synthesized via parallel medicinal chemistry (PMC) and screened for MLLT1 binding. Subsequent SAR studies led to iterative MLLT1/3 binding and selectivity improvements, culminating in the discovery of PFI-6. PFI-6 demonstrates good affinity and selectivity for MLLT1/3 vs. other human YD proteins (YEATS2/4) and engages MLLT3 in cells. Small-molecule X-ray co-crystal structures of two molecules, including PFI-6, bound to the YD of MLLT1/3 are also described. PFI-6 may be a useful tool molecule to better understand the biological effects associated with modulation of MLLT1/3.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Nucleares / Histonas Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteínas Nucleares / Histonas Límite: Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido