Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2
Knutson, SK et al. (2013) PNAS. doi:10.1073/pnas.1303800110

• In this article Epizyme scientists demonstrate the effectiveness of a potent, selective EZH2 inhibitor in specifically killing malignant rhabdoid tumors that are deficient in the protein SNF5, both in cell culture and in rodent xenograft models. This work demonstrates for the first time that sensitivity to HMT inhibition can be conferred by genetic alterations distinct from the direct pathway of HMT action . Additionally, this work demonstrates for the first time the effectiveness of an EZH2 inhibitor in a solid tumor indication.

 

Drugging the human methylome: an emerging modality for reversible control of aberrant gene transcription
Wigle TJ, Copeland RA. (2013) Curr Opin Chem Biol. doi: 10.1016/j.cbpa.2013.03.035

• This article introduces the concept of the "methylome" - a coordinated network of proteins responsible for depositing, removing and recognizing methyl marks on histones - as a control mechanism for gene transcription. The article goes on to describe the role of different methylome constituent proteins in human diseases.

 

This poster, presented at the 2012 ASH meeting (Atlanta, GA, December, 2012) summarized the preclinical characterization of the potent, selective EZH2 inhibitor EPZ-6438 (E7438), which is being advanced to human clinical trials.

 

This poster, presented at the 2012 ASH meeting (Atlanta, GA, December, 2012) summarized the preclinical characterization of the potent, selective DOT1L inhibitor EPZ-5676, for which a phase 1 clinical trial has been initiated.

 

Epizyme announces that the "Nature Reprint Collection: Epigenetics" from Nature Publishing Group is now available online at www.nature.com/reprintcollections/epigenetics.

• • This collection, selected by Robert A. Copeland, Ph.D., our EVP and CSO, includes breakthrough work in the field of personalized therapeutics directed at epigenetic targets with a focus on histone methylation.  The ability to identify true oncogenes and to direct research and clinical development at the genetically defined cancers that they drive is a transformational force in the biopharma industry.  Epizyme is pleased to be able to contribute to this vital effort with the present collection.
  
  

Targeting Genetic Alterations in Protein Methyltransferases for Personalized Cancer Therapeutics

Copeland RA, Moyer MP, Richon VM. (2012) Oncogene. 32:939-946.

• • This publication provides a comprehensive review of the histone methyltransferase (HMT) target class, the genetic alterations in these enzymes that drive specific human cancers and the ongoing efforts to identify and develop potent, selective inhibitors of these enzymes as the basis for novel, personalized cancer therapeutics.
  
  

A Selective Inhibitor of EZH2 Blocks H3K27 Methylation and Kills Mutant Lymphoma Cells

Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Porter Scott M, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW.  (2012) Nature Chemical Biology 8 890-8.

• This paper describes the very first example of a potent, selective and cell-permeable small molecule inhibitor of the histone methyltransferase, EZH2. The compound was used to elucidate the biological consequences of EZH2 inhibition in non-Hodgkin lymphoma cells and provides unequivocal proof that genetic alterations in this enzyme can confer a unique vulnerability to cancer cells for treatments based on selective EZH2 inhibition.
  
  

Epigenetics: Stopping a Chromatin Enzyme

Simon JA. Nature Chemical Biology. [10.1038/nchembio.1088]. 2012;8(11):875-6.

• In this perspective piece, commissioned by the Nature Publishing Group, Professor Jeffrey A. Simon (University of Minnesota) provides a clear description of the impact of the EZH2 inhibitor reported by Epizyme in Knutson et al (see paper above).  Simon stresses the importance of this compound as a much-needed tool for unraveling the complex biology of chromatin modification, the increasing validation of EZH2 as a therapeutic target for genetically defined cancers, and as a harbinger of the near-term utility of HMT inhibitors as personalized therapeutics.
  
  

Selective Killing of Mixed Lineage Leukemia Cells by a Potent Small-Molecule DOT1L Inhibitor

Daigle SR, Olhave EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng J-C, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM. (2011) Cancer Cell.  20:53-65.

 

• This paper provided the first demonstration of in vivo anti-cancer activity for a potent and selective small molecule inhibitor of a human protein methyltransferase, DOT1L.
  
  

Chemogenetic Analysis of Human Protein Methyltransferases

Click here to view video

Richon VM, Johnston D, Sneeringer CJ, Jin L, Majer CJ, Elliston K, Jerva LF, Scott MP, Copeland RA. Chem. Biol. Drug Design (2011) 78:199-210.

 

• This paper presented a comprehensive survey of the human genome and established the constituency of protein methyltransferases (PMTs) in humans.  It also defined the structural relatedness among human PMTs, thus providing a roadmap for study of PMT inhibitor selectivity.
  
  

Coordinated Activities of Wild-type Plus Mutant EZH2 Drive Tumor-Associated Hypertrimethylation of Lysine 27 on Histone H3 (H3K27) in Human B-Cell Lymphomas (Full Paper)

Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, Copeland RA. (2010) Proc. Natl. Acad. Sci. USA 107:20980-20985.

 

• This paper established a novel mechanism for pathogenesis in human cancer:  the requisite coupling of heterozygous activity between a wild-type and disease-associated mutant enzyme.  It also defined a cogent rationale for drug discovery efforts against the PMT EZH2 for treatment of mutant-bearing patients with non-Hodgkin’s lymphoma.
  
  

Protein Methyltransferases as a Target Class for Drug Discovery

Copeland RA, Solomon ME, Richon VM. (2009) Nat Rev Drug Discov. 8:724-32.

 

• This paper established the biological, biochemical and medicinal chemical rationales for pursuing the protein methyltranserases as a target class for drug discovery.
  
  

 

Publications

 

Abrogation of MLL–AF10 and CALM–AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l
Chen L, Deshpande AJ, Banka D, Bernt KM, Dias S, Buske C, Olhava EJ, Daigle SR, Richon VM, Pollock RM, Armstrong SA. (2013) Leukemia 27:813-822.

 

Conformational Adaptation Drives Potent, Selective and Durable Inhibition of the Human Protein Methyltransferase DOT1L.

Basavapathruni A, Jin L, Daigle SR, Majer CR, Therkelsen CA, Wigle TJ, Kuntz KW, Chesworth R, Pollock RM, Scott MP, Moyer MP, Richon VM, Copeland RA, Olhava EJ. (2012) Chem Biol Drug Des. 80:971-980.

 

A687V EZH2 is a gain-of-function mutation found in lymphoma patients

Majer, C.R. et al. (2012) FEBS Lett. 586:3448-3451
 

Protein Methyltransferases as Targets for Personalized Cancer Therapeutics
Richon VM, Moyer MP, Copeland RA. American Association for Cancer Research Annual Meeting 2012: Education Book 107-112.

 

The Human Protein Methyltransferases Poster Sponsored by EpizymeNature Chemical Biology 2011

Click here to view a video about our HMTome "family tree" publication in Chem. Biol. Drug Design 2011 Aug; 78 (2): 199-210.