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Astemizole arrests the proliferation of cancer cells by disrupting the EZH2-EED interaction of polycomb repressive complex 2.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2014 Nov 26; Vol. 57 (22), pp. 9512-21. Date of Electronic Publication: 2014 Nov 12. - Publication Year :
- 2014
-
Abstract
- Polycomb Repressive Complex 2 (PRC2) modulates the chromatin structure and transcriptional repression by trimethylation lysine 27 of histone H3 (H3K27me3), a process that necessitates the protein-protein interaction (PPI) between the catalytic subunit EZH2 and EED. Deregulated PRC2 is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic cancer therapy. However, until now, there have been no reported small molecule compounds targeting the EZH2-EED interactions. In the present study, we identified astemizole, an FDA-approved drug, as a small molecule inhibitor of the EZH2-EED interaction of PRC2. The disruption of the EZH2-EED interaction by astemizole destabilizes the PRC2 complex and inhibits its methyltransferase activity in cancer cells. Multiple lines of evidence have demonstrated that astemizole arrests the proliferation of PRC2-driven lymphomas primarily by disabling the PRC2 complex. Our findings demonstrate the chemical tractability of the difficult PPI target by a small molecule compound, highlighting the therapeutic promise for PRC2-driven human cancers via targeted destruction of the EZH2-EED complex.
- Subjects :
- Binding, Competitive
Catalysis
Catalytic Domain
Cell Line, Tumor
Cell Proliferation
Cell Survival
Disease Progression
Enhancer of Zeste Homolog 2 Protein
Histones chemistry
Humans
Lymphoma metabolism
Magnetic Resonance Spectroscopy
Methylation
Models, Molecular
Molecular Docking Simulation
Neoplasms genetics
Protein Interaction Mapping
Protein Processing, Post-Translational
Astemizole chemistry
Neoplasms drug therapy
Polycomb Repressive Complex 2 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 57
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25369470
- Full Text :
- https://doi.org/10.1021/jm501230c