Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Jay H. Kalin, Muzhou Wu, Andrea V. Gomez, Yun Song, Jayanta Das, Dawn Hayward, Nkosi Adejola, Mingxuan Wu, Izabela Panova, Hye Jin Chung, Edward Kim, Holly J. Roberts, Justin M. Roberts, Polina Prusevich, Jeliazko R. Jeliazkov, Shourya S. Roy Burman, Louise Fairall, Charles Milano, Abdulkerim Eroglu, Charlotte M. Proby, Albena T. Dinkova-Kostova, Wayne W. Hancock, Jeffrey J. Gray, James E. Bradner, Sergio Valente, Antonello Mai, Nicole M. Anders, Michelle A. Rudek, Yong Hu, Byungwoo Ryu, John W. R. Schwabe (), Andrea Mattevi (), Rhoda M. Alani () and Philip A. Cole ()
Additional contact information
Jay H. Kalin: Harvard Medical School and Brigham and Women’s Hospital
Muzhou Wu: Boston University School of Medicine
Andrea V. Gomez: University of Pavia
Yun Song: University of Leicester
Jayanta Das: Johns Hopkins University School of Medicine
Dawn Hayward: Johns Hopkins University School of Medicine
Nkosi Adejola: Johns Hopkins University School of Medicine
Mingxuan Wu: Harvard Medical School and Brigham and Women’s Hospital
Izabela Panova: Boston University School of Medicine
Hye Jin Chung: Boston University School of Medicine
Edward Kim: Boston University School of Medicine
Holly J. Roberts: Boston University School of Medicine
Justin M. Roberts: Dana-Farber Cancer Institute
Polina Prusevich: Johns Hopkins University School of Medicine
Jeliazko R. Jeliazkov: Johns Hopkins University
Shourya S. Roy Burman: Johns Hopkins University
Louise Fairall: University of Leicester
Charles Milano: University of Leicester
Abdulkerim Eroglu: Johns Hopkins University School of Medicine
Charlotte M. Proby: University of Dundee
Albena T. Dinkova-Kostova: Johns Hopkins University School of Medicine
Wayne W. Hancock: University of Pennsylvania School of Medicine
Jeffrey J. Gray: Johns Hopkins University
James E. Bradner: Dana-Farber Cancer Institute
Sergio Valente: Sapienza University of Rome
Antonello Mai: Sapienza University of Rome
Nicole M. Anders: Johns Hopkins University School of Medicine
Michelle A. Rudek: Johns Hopkins University School of Medicine
Yong Hu: BioDuro LLC
Byungwoo Ryu: Boston University School of Medicine
John W. R. Schwabe: University of Leicester
Andrea Mattevi: University of Pavia
Rhoda M. Alani: Boston University School of Medicine
Philip A. Cole: Harvard Medical School and Brigham and Women’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02242-4

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