期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 6, 页码 1324-1334出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb400133J
关键词
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资金
- University Cancer Research Fund
- Carolina Partnership from University of North Carolina at Chapel Hill
- V Foundation for Cancer Research
- Canada Foundation for Innovation [1097737]
- Eli Lilly Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Novartis Research Foundation
- Pfizer
- AbbVie
- Takeda
- Janssen
- Boehringer Ingelheim
- Wellcome Trust
- Genome Canada [OGI-055]
- NIH/NCI Pathway to Independence Award in Cancer Research [R00CA151683]
- American Cancer Society [119169-PF-10-183-01-TBE]
- National Institutes of Health [GM057464, GM094663]
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 wildtype and mutant EZH2 as well as EZH1, a closely related H3K27 methyltransferase that shares 96% sequence identity with EZH2 in their respective catalytic domahis. 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 M cells and selectively killed diffused large B cell lymphoma cell lines harboring the EZH2(Y64IN) 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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