期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 21, 页码 8931-8942出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm401480r
关键词
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资金
- National Institute of General Medical Sciences of the National Institutes of Health [R01GM103893]
- University Cancer Research Fund
- University of North Carolina at Chapel Hill
- V Foundation for Cancer Research
- Structural Genomics Consortium, a registered charity [1097737]
- Canada Foundation for Innovation
- Eli Lilly Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Novartis Research Foundation
- Pfizer
- AbbVie
- Takeda
- Janssen
- Boehringer Ingelheim
- Wellcome Trust
Among epigenetic writers, readers, and erasers, the lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9me2) and nonhistone proteins, have been implicated in a variety of human diseases. A toolkit of well-characterized chemical probes will allow biological and disease hypotheses concerning these proteins to be tested in cell-based and animal models with high confidence. We previously discovered potent and selective G9a/GLP inhibitors including the cellular chemical probe UNC0638, which displays an excellent separation of functional potency and cell toxicity. However, this inhibitor is not suitable for animal studies due to its poor pharmacokinetic (PK) properties. Here, we report the discovery of the first G9a and GLP in vivo chemical probe UNC0642, which not only maintains high in vitro and cellular potency, low cell toxicity, and excellent selectivity, but also displays improved in vivo PK properties, making it suitable for animal studies.
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