| A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. | |
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MedLine Citation:
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PMID: 23023262 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sarah K Knutson; Tim J Wigle; Natalie M Warholic; Christopher J Sneeringer; Christina J Allain; Christine R Klaus; Joelle D Sacks; Alejandra Raimondi; Christina R Majer; Jeffrey Song; Margaret Porter Scott; Lei Jin; Jesse J Smith; Edward J Olhava; Richard Chesworth; Mikel P Moyer; Victoria M Richon; Robert A Copeland; Heike Keilhack; Roy M Pollock; Kevin W Kuntz |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-9-30 |
Journal Detail:
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Title: Nature chemical biology Volume: - ISSN: 1552-4469 ISO Abbreviation: Nat. Chem. Biol. Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-10-1 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101231976 Medline TA: Nat Chem Biol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Epizyme, Inc., Cambridge, Massachusetts, USA. [2]. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PubChem-Substance/144100026; 144100025; 144100027; 144100028 |
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| MeSH Terms | |
Descriptor/Qualifier:
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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