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. ProbyAlbena T. Dinkova-Kostova, Wayne W. Hancock, Jeffrey J Gray, James E. Bradner, Sergio Valente, Antonello Mai, Nicole Anders, Michelle Rudek-Renaut, Yong Hu, Byungwoo Ryu, John W.R. Schwabe, Andrea Mattevi, Rhoda M. Alani, Philip A. Cole

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number53
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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Histone Demethylases
Histone Deacetylase Inhibitors
Histone Deacetylases
inhibitors
Melanoma
Tranylcypromine
Poisons
Melanocytes
Keratinocytes
Heterografts
Epigenomics
Gene expression
Tumors
Squamous Cell Carcinoma
gene expression
Gene Expression
Cell Line
Skin
mice
tumors

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Kalin, J. H., Wu, M., Gomez, A. V., Song, Y., Das, J., Hayward, D., ... Cole, P. A. (2018). Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nature Communications, 9(1), [53]. https://doi.org/10.1038/s41467-017-02242-4

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. / Kalin, Jay H.; Wu, Muzhou; Gomez, Andrea V.; Song, Yun; Das, Jayanta; Hayward, Dawn; Adejola, Nkosi; Wu, Mingxuan; Panova, Izabela; Chung, Hye Jin; Kim, Edward; Roberts, Holly J.; Roberts, Justin M.; Prusevich, Polina; Jeliazkov, Jeliazko R.; Roy Burman, Shourya S.; Fairall, Louise; Milano, Charles; Eroglu, Abdulkerim; Proby, Charlotte M.; Dinkova-Kostova, Albena T.; Hancock, Wayne W.; Gray, Jeffrey J; Bradner, James E.; Valente, Sergio; Mai, Antonello; Anders, Nicole; Rudek-Renaut, Michelle; Hu, Yong; Ryu, Byungwoo; Schwabe, John W.R.; Mattevi, Andrea; Alani, Rhoda M.; Cole, Philip A.

In: Nature Communications, Vol. 9, No. 1, 53, 01.12.2018.

Research output: Contribution to journalArticle

Kalin, JH, Wu, M, Gomez, AV, Song, Y, Das, J, Hayward, D, Adejola, N, Wu, M, Panova, I, Chung, HJ, Kim, E, Roberts, HJ, Roberts, JM, Prusevich, P, Jeliazkov, JR, Roy Burman, SS, Fairall, L, Milano, C, Eroglu, A, Proby, CM, Dinkova-Kostova, AT, Hancock, WW, Gray, JJ, Bradner, JE, Valente, S, Mai, A, Anders, N, Rudek-Renaut, M, Hu, Y, Ryu, B, Schwabe, JWR, Mattevi, A, Alani, RM & Cole, PA 2018, 'Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors', Nature Communications, vol. 9, no. 1, 53. https://doi.org/10.1038/s41467-017-02242-4
Kalin, Jay H. ; Wu, Muzhou ; Gomez, Andrea V. ; Song, Yun ; Das, Jayanta ; Hayward, Dawn ; Adejola, Nkosi ; Wu, Mingxuan ; Panova, Izabela ; Chung, Hye Jin ; Kim, Edward ; Roberts, Holly J. ; Roberts, Justin M. ; Prusevich, Polina ; Jeliazkov, Jeliazko R. ; Roy Burman, Shourya S. ; Fairall, Louise ; Milano, Charles ; Eroglu, Abdulkerim ; Proby, Charlotte M. ; Dinkova-Kostova, Albena T. ; Hancock, Wayne W. ; Gray, Jeffrey J ; Bradner, James E. ; Valente, Sergio ; Mai, Antonello ; Anders, Nicole ; Rudek-Renaut, Michelle ; Hu, Yong ; Ryu, Byungwoo ; Schwabe, John W.R. ; Mattevi, Andrea ; Alani, Rhoda M. ; Cole, Philip A. / Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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