Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)

H. Ümit Kaniskan, Mohammad S. Eram, Kehao Zhao, Magdalena M. Szewczyk, Xiaobao Yang, Keith Schmidt, Xiao Luo, Sean Xiao, Miao Dai, Feng He, Irene Zang, Ying Lin, Fengling Li, Elena Dobrovetsky, David Smil, Sun Joon Min, Jennifer Lin-Jones, Matthieu Schapira, Peter Atadja, En LiDalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Peter J. Brown, Feng Liu, Zhengtian Yu, Masoud Vedadi, Jian Jin

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 (IC 50 values: ∼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.

Original languageEnglish
Pages (from-to)1204-1217
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - 8 Feb 2018


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