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      headline:Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors
      description:Here we report corin, a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin potently targets the CoREST complex and shows more sustained inhibition of CoREST complex HDAC activity compared with entinostat. Cell-based experiments demonstrate that corin exhibits a superior anti-proliferative profile against several melanoma lines and cutaneous squamous cell carcinoma lines compared to its parent monofunctional inhibitors but is less toxic to melanocytes and keratinocytes. CoREST knockdown, gene expression, and ChIP studies suggest that corin’s favorable pharmacologic effects may rely on an intact CoREST complex. Corin was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that may show preferential targeting of particular epigenetic regulatory complexes and offer unique therapeutic opportunities. Alteration of the epigenetic landscape has been implicated in several disease processes, where targeting histone modifiers may have therapeutic applications. Here the authors report a bifunctional small molecule inhibitor that simultaneously targets the deacetylase (HDAC1) and demethylase (LSD1) activities of the CoREST complex.
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      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women’s Hospital, Boston, USA
      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Program in Molecular Biophysics, Johns Hopkins University, Baltimore, USA
      name:Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
      name:Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
      name:Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Division of Cancer Research, Jacqui Wood Cancer Centre, University of Dundee, Dundee, UK
      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Division of Cancer Research, Jacqui Wood Cancer Centre, University of Dundee, Dundee, UK
      name:Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA
      name:Program in Molecular Biophysics, Johns Hopkins University, Baltimore, USA
      name:Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, USA
      name:Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Pasteur Institute, Cenci-Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
      name:Pasteur Institute, Cenci-Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
      name:Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
      name:Department of Oncology, BioDuro LLC, Shanghai, China
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Department of Molecular and Cell Biology, University of Leicester, Leicester, UK
      name:Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
      name:Department of Dermatology, Boston University School of Medicine, Boston, USA
      name:Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women’s Hospital, Boston, USA
      name:Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, USA

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