Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.pdf (1.61 MB)
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Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

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journal contribution
posted on 26.04.2018, 14:53 by J. H. Kalin, M. Wu, A. V. Gomez, Yun Song, J. Das, D. Hayward, N. Adejola, I. Panova, H. J. Chung, E. Kim, H. J. Roberts, J. M. Roberts, P. Prusevich, J. R. Jeliazkov, S. S. Roy Burman, Louise Fairall, Charles Milano, A. Eroglu, C. M. Proby, A. T. Dinkova-Kostova, W. W. Hancock, J. J. Gray, J. E. Bradner, S. Valente, A. Mai, N. M. Anders, M. A. Rudek, Y. Hu, B. Ryu, John W. R. Schwabe, A. Mattevi, R. M. Alani, P. A. Cole
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.

History

Citation

Nature Communications, 2018, 9:53

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Nature Communications

Publisher

Nature Publishing Group

eissn

2041-1723

Acceptance date

14/11/2017

Copyright date

2018

Available date

26/04/2018

Publisher version

http://www.nature.com/articles/s41467-017-02242-4

Language

en