期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 7, 页码 3697-3706出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c02160
关键词
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资金
- U.S. National Institutes of Health [R01GM122749, P30CA196521]
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada through Ontario Genomics Institute [1097737, OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA, Darmstadt, Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Research, Innovation and Science (MRIS) [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737, 106169/ZZ14/Z]
- National Institutes of Health SIG grant [1S10OD025132-01A1]
- Eli Lilly and Company
(R)-2 is a potent and highly selective inhibitor of PRMT6, binding to an induced allosteric pocket. It shows outstanding selectivity for PRMT6 over other methyltransferases and can be used as a valuable tool for further investigation of PRMT6 functions in health and disease.
Protein arginine methyltransferase 6 (PRMT6) catalyzes monomethylation and asymmetric dimethylation of arginine residues in various proteins, plays important roles in biological processes, and is associated with multiple cancers. To date, a highly selective PRMT6 inhibitor has not been reported. Here we report the discovery and characterization of a first-in-class, highly selective allosteric inhibitor of PRMT6, (R)-2 (SGC6870). (R)-2 is a potent PRMT6 inhibitor (IC50 = 77 +/- 6 nM) with outstanding selectivity for PRMT6 over a broad panel of other methyltransferases and nonepigenetic targets. Notably, the crystal structure of the PRMT6-(R)-2 complex and kinetic studies revealed (R)-2 binds a unique, induced allosteric pocket. Additionally, (R)-2 engages PRMT6 and potently inhibits its methyltransferase activity in cells. Moreover, (R)-2's enantiomer, (S)-2 (SGC6870N), is inactive against PRMT6 and can be utilized as a negative control. Collectively, (R)-2 is a well-characterized PRMT6 chemical probe and a valuable tool for further investigating PRMT6 functions in health and disease.
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