Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2.
Sharad K. Verma,Xinrong Tian,Louis V. LaFrance,Celine Duquenne,Dominic Suarez,Kenneth A. Newlander,Stuart Paul Romeril,Joelle Lorraine Burgess,Seth W. Grant,Brackley James,Alan P. Graves,Daryl A. Scherzer,Art Shu,Christine Thompson,Heidi M. Ott,Glenn S. Van Aller,Carl A. Machutta,Elsie Diaz,Yong Jiang,Johnson Neil W,Steven D. Knight,Ryan G. Kruger,Michael T. McCabe,Dashyant Dhanak,Peter J. Tummino,Caretha L. Creasy,William H. Miller +26 more
TLDR
This work has identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 and GSK343, which are small molecule chemical tools that would be useful to further explore the biology of EZh2.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.read more
Citations
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Journal ArticleDOI
Targeting EZH2 in cancer
TL;DR: A unifying perspective is synthesized that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription.
Journal ArticleDOI
EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation
Wendy Béguelin,Relja Popovic,Matt Teater,Yanwen Jiang,Karen L. Bunting,Monica Rosen,Hao Shen,Shao Ning Yang,Ling Wang,Teresa Ezponda,Eva Martinez-Garcia,Haikuo Zhang,Yupeng Zheng,Sharad K. Verma,Michael T. McCabe,Heidi M. Ott,Glenn S. Van Aller,Ryan G. Kruger,Yan Liu,Charles F. McHugh,David Scott,Young Rock Chung,Neil L. Kelleher,Rita Shaknovich,Caretha L. Creasy,Randy D. Gascoyne,Kwok-Kin Wong,Leandro Cerchietti,Ross L. Levine,Omar Abdel-Wahab,Jonathan D. Licht,Olivier Elemento,Ari Melnick +32 more
TL;DR: GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell(ABC)-type DLBCLS, thus clarifying the therapeutic scope of EZh2 targeting.
Journal ArticleDOI
Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas
Sebastian Bender,Sebastian Bender,Yujie Tang,Anders Lindroth,Volker Hovestadt,David T.W. Jones,Marcel Kool,Marc Zapatka,Paul A. Northcott,Dominik Sturm,Wei Wang,Bernhard Radlwimmer,Jonas W. Højfeldt,Nathalene Truffaux,David Castel,Simone Schubert,Marina Ryzhova,Huriye Seker-Cin,Jan Gronych,Pascal-David Johann,Pascal-David Johann,Sebastian Stark,Sebastian Stark,Jochen Meyer,Jochen Meyer,Till Milde,Till Milde,Martin U. Schuhmann,Martin Ebinger,Camelia M. Monoranu,Anitha Ponnuswami,S. Chen,Chris Jones,Olaf Witt,Olaf Witt,V. Peter Collins,Andreas von Deimling,Andreas von Deimling,Nada Jabado,Stéphanie Puget,Jacques Grill,Kristian Helin,Andrey Korshunov,Andrey Korshunov,Peter Lichter,Michelle Monje,Christoph Plass,Yoon Jae Cho,Stefan M. Pfister,Stefan M. Pfister +49 more
TL;DR: It is shown that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs, and it is demonstrated that this is caused by aberrant recruitment of the PRC2 complex to K 27M mutant H3.3.
Journal ArticleDOI
Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
TL;DR: The aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression are summarized and the development of inhibitors of or drugs targeted at epigenetic enzymes are highlighted.
Journal ArticleDOI
An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1.
Kyle D. Konze,Anqi Ma,Fengling Li,Dalia Barsyte-Lovejoy,Trevor Parton,Christopher J. MacNevin,Feng Liu,Cen Gao,Xi Ping Huang,Ekaterina Kuznetsova,Marie Rougie,Alice Jiang,Samantha G. Pattenden,Jacqueline L. Norris,Lindsey I. James,Bryan L. Roth,Peter Brown,Stephen V. Frye,Cheryl H. Arrowsmith,Klaus M. Hahn,Gang Greg Wang,Masoud Vedadi,Jian Jin +22 more
TL;DR: UNC1999 was the first orally bioavailable inhibitor that has high in vitro potency for wild-type and mutant EZH2 as well as EzH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZh2 in their respective catalytic domains.
References
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TL;DR: The surface of nucleosomes is studded with a multiplicity of modifications that can dictate the higher-order chromatin structure in which DNA is packaged and can orchestrate the ordered recruitment of enzyme complexes to manipulate DNA.
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TL;DR: Dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.
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EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells
Celina G. Kleer,Qi Cao,Sooryanarayana Varambally,Ronglai Shen,Ichiro Ota,Scott A. Tomlins,Debashis Ghosh,Richard George Antonius Bernardus Sewalt,Arie P. Otte,Daniel F. Hayes,Michael S. Sabel,Donna L. Livant,Stephen J. Weiss,Mark A. Rubin,Arul M. Chinnaiyan +14 more
TL;DR: Tissue microarray analysis demonstrated that EZH2 protein levels were strongly associated with breast cancer aggressiveness and provided compelling evidence for a functional link between dysregulated cellular memory, transcriptional repression, and neoplastic transformation.
Journal ArticleDOI
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations.
Michael T. McCabe,Heidi M. Ott,Gopinath Ganji,Susan Korenchuk,Christine Thompson,Glenn S. Van Aller,Yan Liu,Alan P. Graves,Anthony Della Pietra,Elsie Diaz,Louis V. LaFrance,Mellinger Mark,Celine Duquenne,Xinrong Tian,Ryan G. Kruger,Charles F. McHugh,Martin Brandt,William H. Miller,Dashyant Dhanak,Sharad K. Verma,Peter J. Tummino,Caretha L. Creasy +21 more
TL;DR: GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.
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