A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells
| Autor: | Natalie Warholic, Christina R. Majer, Christopher J. Sneeringer, Christina J. Allain, Edward J. Olhava, Mikel P. Moyer, Sarah K. Knutson, Heike Keilhack, J. Joshua Smith, Lei Jin, Joelle D. Sacks, Robert A. Copeland, Tim J. Wigle, Richard Chesworth, Margaret Porter Scott, Jeffrey Song, Alejandra Raimondi, Kevin Wayne Kuntz, Roy M. Pollock, Victoria M. Richon, Christine Klaus |
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| Rok vydání: | 2012 |
| Předmět: |
Indazoles
Methyltransferase Lymphoma Pyridones Mutant Antineoplastic Agents macromolecular substances Methylation Histones Structure-Activity Relationship medicine Humans Point Mutation Enhancer of Zeste Homolog 2 Protein Epigenetics Enzyme Inhibitors Molecular Biology Cell Proliferation Cell Death Dose-Response Relationship Drug Molecular Structure biology Lysine Point mutation Cell Cycle fungi EZH2 Polycomb Repressive Complex 2 Cell Biology medicine.disease Chromatin Cancer research biology.protein PRC2 |
| Zdroj: | Nature Chemical Biology. 8:890-896 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | EZH2 catalyzes trimethylation of histone H3 lysine 27 (H3K27). Point mutations of EZH2 at Tyr641 and Ala677 occur in subpopulations of non-Hodgkin's lymphoma, where they drive H3K27 hypertrimethylation. Here we report the discovery of EPZ005687, a potent inhibitor of EZH2 (K(i) of 24 nM). EPZ005687 has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1. The compound 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. These data suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered. |
| Databáze: | OpenAIRE |
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