Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 3, Pages 1204-1217Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01674
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Funding
- U.S. National Institutes of Health [R01GM122749, R01HD088626, R01CA218600]
- National Natural Science Foundation of China [21302134]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
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PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell-active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC50 values: similar to 10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3.
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