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A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3)

Kaniskan, H. Umit , Szewczyk, Magdalena , Yu, Zhengtian, Eram, Mohammad S. , Luo, Xiao, Yang, Xiaobao, Schmidt, Keith , Dai, Miao, He, Feng, Zang, Irene, Li, Fengling, Smil, David, Dong, Aiping, Landon, Melissa, Lin-Jones, Jennifer, Huang, Xi-Ping, Roth, Bryan, Schapira, Matthieu, Atadja, Peter, Barsyte-Lovejoy, Dalia , Arrowsmith, Cherry H., Brown, Peter, Zhao, Kehao, Jin, Jian and Vedadi, Masoud (2015) A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angewandte Chemie (International ed. in English), 54 (17). pp. 5166-5170. ISSN 1521-3773


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 cell-active 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 (IC50 =31±2 nM, KD =53±2 nM) with outstanding selectivity (selective against 31 other methyltransferases 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.

Item Type: Article
Keywords: allosteric inhibition chemical probes enzyme inhibitors histone methylation X-ray diffraction
Date Deposited: 28 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45


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