| Literature DB >> 29302039 |
Jay H Kalin1,2, Muzhou Wu3, Andrea V Gomez4, Yun Song5, Jayanta Das2, Dawn Hayward2, Nkosi Adejola2, Mingxuan Wu1,2, Izabela Panova3, Hye Jin Chung3, Edward Kim3, Holly J Roberts3, Justin M Roberts6, Polina Prusevich2, Jeliazko R Jeliazkov7, Shourya S Roy Burman8, Louise Fairall5, Charles Milano5, Abdulkerim Eroglu2, Charlotte M Proby9, Albena T Dinkova-Kostova2,9, Wayne W Hancock10, Jeffrey J Gray7,8,11, James E Bradner6, Sergio Valente12, Antonello Mai12, Nicole M Anders11, Michelle A Rudek11, Yong Hu13, Byungwoo Ryu3, John W R Schwabe14, Andrea Mattevi15, Rhoda M Alani16, Philip A Cole17,18.
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.Entities:
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Year: 2018 PMID： 29302039 PMCID： PMC5754352 DOI： 10.1038/s41467-017-02242-4
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919