Journal ArticleDOI
An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED
Wei Qi,Kehao Zhao,Justin Gu,Ying Huang,Youzhen Wang,Hailong Zhang,Man Zhang,Jeff Zhang,Zhengtian Yu,Ling Li,Lin Teng,Shannon Chuai,Chao Zhang,Mengxi Zhao,Ho Man Chan,Zijun Chen,Douglas Fang,Qi Fei,Leying Feng,Lijian Feng,Yuan Gao,Hui Ge,Xinjian Ge,Guobin Li,Andreas Lingel,Ying Lin,Yueqin Liu,Fangjun Luo,Minlong Shi,Long Wang,Zhaofu Wang,Yanyan Yu,Jue Zeng,Chenhui Zeng,Lijun Zhang,Qiong Zhang,Shaolian Zhou,Counde Oyang,Peter Atadja,En Li +39 more
TLDR
EED226 is reported, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED, and shows similar activity to SAM-competitive inhibitors in blocking H 3K27 methylation ofPRC2 target genes and inducing regression of human lymphoma xenograft tumors.Abstract:
Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.read more
Citations
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Journal ArticleDOI
Targeted protein degradation: expanding the toolbox.
TL;DR: Opportunities and challenges for expanding the applicability of targeted protein degradation are discussed, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.
Journal ArticleDOI
Small molecules in targeted cancer therapy: advances, challenges, and future perspectives.
Lei Zhong,Y. Li,Liang Xiong,Wen-Jing Wang,Ming Wu,Ting Yuan,Wei Yang,Chenyu Tian,Zhuang Miao,Tianqi Wang,Shengyong Yang +10 more
TL;DR: A comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification is conducted, which presents all the approved drugs as well as important drug candidates in clinical trials for each target, and discusses the current challenges.
Journal ArticleDOI
EZH2: a novel target for cancer treatment.
Ran Duan,Wenfang Du,Weijian Guo +2 more
TL;DR: The structure and action modes of EZH2 are summarized, focusing on up-to-date findings regarding the role of E zeste homolog 2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation.
Journal ArticleDOI
An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Marian L. Burr,Marian L. Burr,Marian L. Burr,Christina E. Sparbier,Christina E. Sparbier,Kah Lok Chan,Kah Lok Chan,Yih-Chih Chan,Ariena Kersbergen,Enid Y.N. Lam,Enid Y.N. Lam,Elizabeth Azidis-Yates,Dane Vassiliadis,Dane Vassiliadis,Charles C. Bell,Charles C. Bell,Omer Gilan,Omer Gilan,Susan Jackson,Lavinia Tan,Lavinia Tan,Stephen Q. Wong,Stephen Q. Wong,Sebastian Hollizeck,Sebastian Hollizeck,Ewa M. Michalak,Ewa M. Michalak,Hannah V. Siddle,Michael T. McCabe,Rab K. Prinjha,Glen R. Guerra,Glen R. Guerra,Benjamin Solomon,Benjamin Solomon,Shahneen Sandhu,Shahneen Sandhu,Sarah-Jane Dawson,Sarah-Jane Dawson,Paul A. Beavis,Paul A. Beavis,Richard W. Tothill,Carleen Cullinane,Carleen Cullinane,Paul J. Lehner,Kate D. Sutherland,Kate D. Sutherland,Mark A. Dawson,Mark A. Dawson +47 more
TL;DR: A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (M HC-I APP), promoting evasion of T cell-mediated immunity.
Journal ArticleDOI
Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy.
TL;DR: This review deals with the recent developments in small molecule inhibitors as potential anti-cancer drugs targeting the epigenetic space and highlights the different types of epigenetic enzymes and protein domains with an emphasis on methylation and acetylation.
References
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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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