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 Proby; Albena 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 ProbyAlbena 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 (Lead / Corresponding author), Andrea Mattevi (Lead / Corresponding author), Rhoda M. Alani (Lead / Corresponding author), Philip A. Cole (Lead / Corresponding author)

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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
Article number	53
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02242-4
Publication status	Published - 4 Jan 2018

Keywords

Chemical tools
Histone post-translational modifications
Multienzyme complexes

ASJC Scopus subject areas

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

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10.1038/s41467-017-02242-4Licence: CC BY

Final Published VersionFinal published version, 1.61 MBLicence: CC BY

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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., Burman, S. S. R., 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), 1-13. Article 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.",

keywords = "Chemical tools, Histone post-translational modifications, Multienzyme complexes",

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

note = "We thank the NIH, the FAMRI foundation, Rete Ematologica Lombarda (FRRB-Regione Lombardia), and the Italian Association for Cancer Research (IG15208 and IG19162) for financial support. This work was supported by PRIN 2016 (prot. 20152TE5PK) (A.M.), NIH (n. R01GM114306) (A.M.), and the EMBO ALTF 261-2011 (A.V.G) funds. J.W.R.S. is a Wellcome Trust Senior Investigator (grant WT100237) and Royal Society Wolfson Research Merit Award Holder. He is also supported by a Biotechnology and Biological Sciences Research Council Project Grant BB/J009598/1 as well as funds from 4SC. A.D-K. is supported by a program award from Cancer Research UK (C20953/A18644), a Biotechnology and Biological Sciences Research Council Project Grant BB/L01923X/1, and a British Skin Foundation Project Grant 33 7015. A.E. was a Kagome Visiting Scholar. We thank Xiaowen Yang and Peter Watson for help with the protein expression and purification. We thank R. Casero for the HCT116 LSD1 knockout cells and D. Meyers, C. Talbot, and J. W. Labonte for helpful advice in regard to synthetic strategy, microarray data analysis, and computational modeling, respectively",

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doi = "10.1038/s41467-017-02242-4",

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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, Burman, SSR, Fairall, L, Milano, C, Eroglu, A, Proby, C , Dinkova-Kostova, A, 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, pp. 1-13. https://doi.org/10.1038/s41467-017-02242-4

TY - JOUR

T1 - Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

AU - Kalin, Jay H.

AU - Wu, Muzhou

AU - Gomez, Andrea V.

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 - Burman, Shourya S. Roy

AU - Fairall, Louise

AU - Milano, Charles

AU - Eroglu, Abdulkerim

AU - Proby, Charlotte

AU - Dinkova-Kostova, Albena

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.

N1 - We thank the NIH, the FAMRI foundation, Rete Ematologica Lombarda (FRRB-Regione Lombardia), and the Italian Association for Cancer Research (IG15208 and IG19162) for financial support. This work was supported by PRIN 2016 (prot. 20152TE5PK) (A.M.), NIH (n. R01GM114306) (A.M.), and the EMBO ALTF 261-2011 (A.V.G) funds. J.W.R.S. is a Wellcome Trust Senior Investigator (grant WT100237) and Royal Society Wolfson Research Merit Award Holder. He is also supported by a Biotechnology and Biological Sciences Research Council Project Grant BB/J009598/1 as well as funds from 4SC. A.D-K. is supported by a program award from Cancer Research UK (C20953/A18644), a Biotechnology and Biological Sciences Research Council Project Grant BB/L01923X/1, and a British Skin Foundation Project Grant 33 7015. A.E. was a Kagome Visiting Scholar. We thank Xiaowen Yang and Peter Watson for help with the protein expression and purification. We thank R. Casero for the HCT116 LSD1 knockout cells and D. Meyers, C. Talbot, and J. W. Labonte for helpful advice in regard to synthetic strategy, microarray data analysis, and computational modeling, respectively

PY - 2018/1/4

Y1 - 2018/1/4

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.

AB - 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.

KW - Chemical tools

KW - Histone post-translational modifications

KW - Multienzyme complexes

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U2 - 10.1038/s41467-017-02242-4

DO - 10.1038/s41467-017-02242-4

M3 - Article

C2 - 29302039

SN - 2041-1723

VL - 9

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 53

ER -

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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Dinkova-Kostova, Albena

Proby, Charlotte

Cite this

Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Profiles

Dinkova-Kostova, Albena

Proby, Charlotte

Cite this