Journal ArticleDOI
The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex
Yupeng He,Sujatha Selvaraju,Michael L. Curtin,Clarissa G. Jakob,Haizhong Zhu,Kenneth M. Comess,Bailin Shaw,Evelyne Lima-Fernandes,Evelyne Lima-Fernandes,Magdalena M. Szewczyk,Dong Cheng,Kelly L Klinge,Huan-Qiu Li,Marina A. Pliushchev,Mikkel Algire,David Maag,Jun Guo,Justin D. Dietrich,Sanjay C. Panchal,Andrew M. Petros,Ramzi F. Sweis,Maricel Torrent,Lance J Bigelow,Guillermo Senisterra,Fengling Li,Steven Kennedy,Qin Wu,Qin Wu,Donald J. Osterling,David Lindley,Wenqing Gao,Scott Galasinski,Dalia Barsyte-Lovejoy,Masoud Vedadi,Masoud Vedadi,Fritz G. Buchanan,Cheryl H. Arrowsmith,Cheryl H. Arrowsmith,Gary G. Chiang,Chaohong Sun,William N. Pappano +40 more
TLDR
A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.Abstract:
Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed in vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein-protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.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
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.
Journal ArticleDOI
Inhibitors of Protein Methyltransferases and Demethylases.
TL;DR: This review covers the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field and discusses challenges, opportunities, and future directions in this emerging, exciting research field.
Journal ArticleDOI
PRC2 is high maintenance
Jia Ray Yu,Jia Ray Yu,Chul Hwan Lee,Chul Hwan Lee,Ozgur Oksuz,Ozgur Oksuz,James M. Stafford,James M. Stafford,Danny Reinberg,Danny Reinberg +9 more
TL;DR: In this review, Yu et al. discuss the recent advances in knowledge of the Polycomb-repressive complex 2 (PRC2) in mammalian systems and discuss important discoveries on Polycomb function derived from model organisms in the context of understanding mammalian PRC2 function.
References
More filters
Journal ArticleDOI
Coot: model-building tools for molecular graphics.
Paul Emsley,Kevin Cowtan +1 more
TL;DR: CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics.
Journal ArticleDOI
Phaser crystallographic software
Airlie J. McCoy,Ralf W. Grosse-Kunstleve,Paul D. Adams,Martyn Winn,Laurent C. Storoni,Randy J. Read +5 more
TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Journal ArticleDOI
Refinement of macromolecular structures by the maximum-likelihood method.
TL;DR: The likelihood function for macromolecular structures is extended to include prior phase information and experimental standard uncertainties and the results derived are consistently better than those obtained from least-squares refinement.
Journal ArticleDOI
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions
E. Krissinel,Kim Henrick +1 more
TL;DR: The present paper describes the SSM algorithm of protein structure comparison in three dimensions, which includes an original procedure of matching graphs built on the protein's secondary-structure elements, followed by an iterative three-dimensional alignment of protein backbone Calpha atoms.
Journal ArticleDOI
Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
Ru Cao,Liangjun Wang,Hengbin Wang,Li Xia,Hediye Erdjument-Bromage,Paul Tempst,Richard S. Jones,Yi Zhang +7 more
TL;DR: The purification and characterization of an EED-EZH2 complex, the human counterpart of the Drosophila ESC-E(Z) complex, is reported, and it is demonstrated that the complex specifically methylates nucleosomal histone H3 at lysine 27 (H3-K27).
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