2. Academic Validation
  3. Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

  • Nat Commun. 2018 Jan 4;9(1):53. doi: 10.1038/s41467-017-02242-4.
Jay H Kalin 1 2,  Muzhou Wu 3,  Andrea V Gomez 4,  Yun Song 5,  Jayanta Das 2,  Dawn Hayward 2,  Nkosi Adejola 2,  Mingxuan Wu 1 2,  Izabela Panova 3,  Hye Jin Chung 3,  Edward Kim 3,  Holly J Roberts 3,  Justin M Roberts 6,  Polina Prusevich 2,  Jeliazko R Jeliazkov 7,  Shourya S Roy Burman 8,  Louise Fairall 5,  Charles Milano 5,  Abdulkerim Eroglu 2,  Charlotte M Proby 9,  Albena T Dinkova-Kostova 2 9,  Wayne W Hancock 10,  Jeffrey J Gray 7 8 11,  James E Bradner 6,  Sergio Valente 12,  Antonello Mai 12,  Nicole M Anders 11,  Michelle A Rudek 11,  Yong Hu 13,  Byungwoo Ryu 3,  John W R Schwabe 14,  Andrea Mattevi 15,  Rhoda M Alani 16,  Philip A Cole 17 18
Affiliations

Affiliations

  • 1 Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • 2 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • 3 Department of Dermatology, Boston University School of Medicine, Boston, MA, 02118, USA.
  • 4 Department of Biology and Biotechnology, University of Pavia, 27100, Pavia, Italy.
  • 5 Department of Molecular and Cell Biology, University of Leicester, Leicester, LE1 9HN, UK.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 7 Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • 8 Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • 9 Division of Cancer Research, Jacqui Wood Cancer Centre, University of Dundee, Dundee, DD1 9SY, UK.
  • 10 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
  • 11 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
  • 12 Pasteur Institute, Cenci-Bolognetti Foundation, Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185, Rome, Italy.
  • 13 Department of Oncology, BioDuro LLC, Shanghai, 200131, China.
  • 14 Department of Molecular and Cell Biology, University of Leicester, Leicester, LE1 9HN, UK. [email protected].
  • 15 Department of Biology and Biotechnology, University of Pavia, 27100, Pavia, Italy. [email protected].
  • 16 Department of Dermatology, Boston University School of Medicine, Boston, MA, 02118, USA. [email protected].
  • 17 Division of Genetics, Departments of Medicine and Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
  • 18 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. [email protected].
PMID: 29302039 DOI: 10.1038/s41467-017-02242-4
Abstract

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.

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