Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2

Sharad K. Verma; Xinrong Tian; Louis V. Lafrance; Céline Duquenne; Dominic P. Suarez; Kenneth A. Newlander; Stuart P. Romeril; Joelle L. Burgess; Seth W. Grant; James A. Brackley; Alan P. Graves; Daryl A. Scherzer; Art Shu; Christine Thompson; Heidi M. Ott; Glenn S. Van Aller; Carl A. MacHutta; Elsie Diaz; Yong Jiang; Neil W. Johnson; Steven D. Knight; Ryan G. Kruger; Michael T. McCabe; Dashyant Dhanak; Peter J. Tummino; Caretha L. Creasy; William H. Miller

doi:10.1021/ml3003346

Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2

Sharad K. Verma, Xinrong Tian, Louis V. Lafrance, Céline Duquenne, Dominic P. Suarez, Kenneth A. Newlander, Stuart P. Romeril, Joelle L. Burgess, Seth W. Grant, James A. Brackley, Alan P. Graves, Daryl A. Scherzer, Art Shu, Christine Thompson, Heidi M. Ott, Glenn S. Van Aller, Carl A. MacHutta, Elsie Diaz, Yong Jiang, Neil W. JohnsonSteven D. Knight, Ryan G. Kruger, Michael T. McCabe, Dashyant Dhanak, Peter J. Tummino, Caretha L. Creasy, William H. Miller

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230 Scopus citations

Abstract

The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-Active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.

Original language	English (US)
Pages (from-to)	1091-1096
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	12
DOIs	https://doi.org/10.1021/ml3003346
State	Published - Dec 13 2012
Externally published	Yes

Keywords

EZH2
Epigenetics
H3K27me3
PRC2
SAM-competitive inhibitor
methyltransferase

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml3003346

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Verma, S. K., Tian, X., Lafrance, L. V., Duquenne, C., Suarez, D. P., Newlander, K. A., Romeril, S. P., Burgess, J. L., Grant, S. W., Brackley, J. A., Graves, A. P., Scherzer, D. A., Shu, A., Thompson, C., Ott, H. M., Van Aller, G. S., MacHutta, C. A., Diaz, E., Jiang, Y., ... Miller, W. H. (2012). Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2. ACS Medicinal Chemistry Letters, 3(12), 1091-1096. https://doi.org/10.1021/ml3003346

Verma, SK, Tian, X, Lafrance, LV, Duquenne, C, Suarez, DP, Newlander, KA, Romeril, SP, Burgess, JL, Grant, SW, Brackley, JA, Graves, AP, Scherzer, DA, Shu, A, Thompson, C, Ott, HM, Van Aller, GS, MacHutta, CA, Diaz, E, Jiang, Y, Johnson, NW, Knight, SD, Kruger, RG, McCabe, MT, Dhanak, D, Tummino, PJ, Creasy, CL & Miller, WH 2012, 'Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2', ACS Medicinal Chemistry Letters, vol. 3, no. 12, pp. 1091-1096. https://doi.org/10.1021/ml3003346

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abstract = "The histone H3-lysine 27 (H3K27) methyltransferase EZH2 plays a critical role in regulating gene expression, and its aberrant activity is linked to the onset and progression of cancer. As part of a drug discovery program targeting EZH2, we have identified highly potent, selective, SAM-competitive, and cell-Active EZH2 inhibitors, including GSK926 (3) and GSK343 (6). These compounds are small molecule chemical tools that would be useful to further explore the biology of EZH2.",

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author = "Verma, {Sharad K.} and Xinrong Tian and Lafrance, {Louis V.} and C{\'e}line Duquenne and Suarez, {Dominic P.} and Newlander, {Kenneth A.} and Romeril, {Stuart P.} and Burgess, {Joelle L.} and Grant, {Seth W.} and Brackley, {James A.} and Graves, {Alan P.} and Scherzer, {Daryl A.} and Art Shu and Christine Thompson and Ott, {Heidi M.} and {Van Aller}, {Glenn S.} and MacHutta, {Carl A.} and Elsie Diaz and Yong Jiang and Johnson, {Neil W.} and Knight, {Steven D.} and Kruger, {Ryan G.} and McCabe, {Michael T.} and Dashyant Dhanak and Tummino, {Peter J.} and Creasy, {Caretha L.} and Miller, {William H.}",

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AU - Suarez, Dominic P.

AU - Newlander, Kenneth A.

AU - Romeril, Stuart P.

AU - Burgess, Joelle L.

AU - Grant, Seth W.

AU - Brackley, James A.

AU - Graves, Alan P.

AU - Scherzer, Daryl A.

AU - Shu, Art

AU - Thompson, Christine

AU - Ott, Heidi M.

AU - Van Aller, Glenn S.

AU - MacHutta, Carl A.

AU - Diaz, Elsie

AU - Jiang, Yong

AU - Johnson, Neil W.

AU - Knight, Steven D.

AU - Kruger, Ryan G.

AU - McCabe, Michael T.

AU - Dhanak, Dashyant

AU - Tummino, Peter J.

AU - Creasy, Caretha L.

AU - Miller, William H.

PY - 2012/12/13

Y1 - 2012/12/13

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Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2

Abstract

Keywords

ASJC Scopus subject areas

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