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An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1
Open accessAbstract
EZH2 or EZH1 is the catalytic subunit of the polycomb repressive complex 2 that catalyzes methylation of histone H3 lysine 27 (H3K27). The trimethylation of H3K27 (H3K27me3) is a transcriptionally repressive post-translational modification. Overexpression of EZH2 and hypertrimethylation of H3K27 have been implicated in a number of cancers. Several selective inhibitors of EZH2 have been reported recently. Herein we disclose UNC1999, 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. UNC1999 was highly selective for EZH2 and EZH1 over a broad range of epigenetic and non-epigenetic targets, competitive with the cofactor SAM and non-competitive with the peptide substrate. This inhibitor potently reduced H3K27me3 levels in cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2(Y641N) mutant. Importantly, UNC1999 was orally bioavailable in mice, making this inhibitor a valuable tool for investigating the role of EZH2 and EZH1 in chronic animal studies. We also designed and synthesized UNC2400, a close analogue of UNC1999 with potency >1,000-fold lower than that of UNC1999 as a negative control for cell-based studies. Finally, we created a biotin-tagged UNC1999 (UNC2399), which enriched EZH2 in pull-down studies, and a UNC1999-dye conjugate (UNC2239) for co-localization studies with EZH2 in live cells. Taken together, these compounds represent a set of useful tools for the biomedical community to investigate the role of EZH2 and EZH1 in health and disease.
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The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex
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Dual Inhibition of EZH2 and EZH1 Sensitizes PRC2-Dependent Tumors to Proteasome Inhibition
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Metadata
- Authors
- Konze, K. D., Ma, A., Li, F., Barsyte-Lovejoy, D., Parton, T., MacNevin, C. J., Liu, F., Gao, C., Huang, X.-P., Kuznetsova, E., Rougie, M., Jiang, A., Pattenden, S. G., Norris, J. L., James, L. I., Roth, B. L., Brown, P. J., Frye, S. V., Arrowsmith, C. H., Hahn, K. M., Wang, G. G., Vedadi, M., & Jin, J.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-04-24
- Volume
- 8
- Issue
- 6
- Pages
- 1324-1334
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- OpenAlex
- W2054301876
- Cited by
- 452
- References
- 10
- FWCI
- 18.69
- Type
- journal article
- Language
- en
- Open access
- green
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