期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 54, 期 17, 页码 5166-5170出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201412154
关键词
allosteric inhibition; chemical probes; enzyme inhibitors; histone methylation; X-ray diffraction
资金
- U.S. National Institutes of Health [R01GM103893]
- AbbVie [1097737]
- Bayer
- Boehringer Ingelheim
- Genome Canada through Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- SGC
PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cellactive PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC5 = 31 perpendicular to 2 nm, K-D = 53 perpendicular to 2 nm) with outstanding selectivity (selective against 31 other methyl-transferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.
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