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. Proby; Albena T. 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; Andrea Mattevi; Rhoda M. Alani; Philip A. Cole

doi:10.1038/s41467-017-02242-4

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 M. Anders, Michelle A. Rudek, Yong Hu, Byungwoo Ryu, John W.R. Schwabe, Andrea Mattevi, Rhoda M. Alani, Philip A. Cole

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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 language	English (US)
Article number	53
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02242-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

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

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Kalin, J. H., Wu, M., Gomez, A. V., Song, Y., Das, J., Hayward, D., Adejola, N., Wu, M., Panova, I., Chung, H. J., Kim, E., Roberts, H. J., Roberts, J. M., Prusevich, P., Jeliazkov, J. R., Roy Burman, S. S., Fairall, L., Milano, C., Eroglu, A., ... Cole, P. A. (2018). Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nature communications, 9(1), Article 53. https://doi.org/10.1038/s41467-017-02242-4

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, NM, Rudek, MA, 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

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title = "Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors",

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.",

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AU - Wu, Muzhou

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AU - Song, Yun

AU - Das, Jayanta

AU - Hayward, Dawn

AU - Adejola, Nkosi

AU - Wu, Mingxuan

AU - Panova, Izabela

AU - Chung, Hye Jin

AU - Kim, Edward

AU - Roberts, Holly J.

AU - Roberts, Justin M.

AU - Prusevich, Polina

AU - Jeliazkov, Jeliazko R.

AU - Roy Burman, Shourya S.

AU - Fairall, Louise

AU - Milano, Charles

AU - Eroglu, Abdulkerim

AU - Proby, Charlotte M.

AU - Dinkova-Kostova, Albena T.

AU - Hancock, Wayne W.

AU - Gray, Jeffrey J.

AU - Bradner, James E.

AU - Valente, Sergio

AU - Mai, Antonello

AU - Anders, Nicole M.

AU - Rudek, Michelle A.

AU - Hu, Yong

AU - Ryu, Byungwoo

AU - Schwabe, John W.R.

AU - Mattevi, Andrea

AU - Alani, Rhoda M.

AU - Cole, Philip A.

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N2 - 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.

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Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

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