Author
Listed:
- Jay H. Kalin
(Harvard Medical School and Brigham and Women’s Hospital
Johns Hopkins University School of Medicine)
- 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
Johns Hopkins University School of Medicine)
- 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
University of Dundee)
- Wayne W. Hancock
(University of Pennsylvania School of Medicine)
- Jeffrey J. Gray
(Johns Hopkins University
Johns Hopkins University
Johns Hopkins University School of Medicine)
- 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
Johns Hopkins University School of Medicine)
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.
Suggested Citation
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 & , 2018.
"Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors,"
Nature Communications, Nature, vol. 9(1), pages 1-13, December.
Handle:
RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02242-4
DOI: 10.1038/s41467-017-02242-4
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