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 ProbyAlbena 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 (Lead / Corresponding author), Andrea Mattevi (Lead / Corresponding author), Rhoda M. Alani (Lead / Corresponding author), Philip A. Cole (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    162 Citations (Scopus)
    302 Downloads (Pure)


    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.

    Original languageEnglish
    Article number53
    Pages (from-to)1-13
    Number of pages13
    JournalNature Communications
    Issue number1
    Publication statusPublished - 4 Jan 2018


    • Chemical tools
    • Histone post-translational modifications
    • Multienzyme complexes

    ASJC Scopus subject areas

    • General Physics and Astronomy
    • General Chemistry
    • General Biochemistry,Genetics and Molecular Biology


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