A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells
Masoud Vedadi,Dalia Barsyte-Lovejoy,Feng Liu,Sylvie Rival-Gervier,Abdellah Allali-Hassani,Viviane Labrie,Tim J. Wigle,Peter A. DiMaggio,Gregory A. Wasney,Alena Siarheyeva,Aiping Dong,Wolfram Tempel,Sun Chong Wang,Sun Chong Wang,Xin Chen,Irene Chau,Thomas J. Mangano,Xi Ping Huang,Catherine Simpson,Samantha G. Pattenden,Jacqueline L. Norris,Dmitri Kireev,Ashutosh Tripathy,Aled M. Edwards,Bryan L. Roth,William P. Janzen,Benjamin A. Garcia,Arturas Petronis,James Ellis,Peter Brown,Stephen V. Frye,Cheryl H. Arrowsmith,Jian Jin +32 more
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TLDR
UNC0638 is reported, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets, and markedly reduced the clonogenicity of MCF7 cells and disproportionately affected several genomic loci encoding microRNAs.Abstract:
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.read more
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Epigenetic protein families: a new frontier for drug discovery
Cheryl H. Arrowsmith,C. Bountra,Paul V. Fish,Kevin Lee,Kevin Lee,Matthieu Schapira,Matthieu Schapira +6 more
TL;DR: The key protein families that mediate epigenetic signalling through the acetylation and methylation of histones are reviewed, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones.
Journal ArticleDOI
Cancer Epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance
TL;DR: The possible role of epigenetic abnormalities as well as genetic alterations in such dynamics and in the creation of cellular heterogeneity in cancers of all types are discussed.
Journal ArticleDOI
A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells
Sarah K. Knutson,Tim J. Wigle,Natalie Warholic,Christopher J. Sneeringer,Christina J. Allain,Christine Klaus,Joelle D. Sacks,Alejandra Raimondi,Christina R. Majer,Jeffrey Song,Margaret Porter Scott,Lei Jin,J. Joshua Smith,Edward J. Olhava,Richard Chesworth,Mikel P. Moyer,Victoria M. Richon,Robert A. Copeland,Heike Keilhack,Roy M. Pollock,Kevin Wayne Kuntz +20 more
TL;DR: The discovery of EPZ005687 is reported, a potent inhibitor of EZH2 that reduces H3K27 methylation in various lymphoma cells; this translates into apoptotic cell killing in heterozygous Tyr641 or Ala677 mutant cells, with minimal effects on the proliferation of wild-type cells.
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.
Journal ArticleDOI
Chromatin proteins and modifications as drug targets
Kristian Helin,Dashyant Dhanak +1 more
TL;DR: A generation of new classes of potent and specific inhibitors for several chromatin-associated proteins have shown promise in preclinical trials, and although the biology of epigenetic regulation is complex, new inhibitors such as these will hopefully be of clinical use in the coming years.
References
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