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

H. Ümit Kaniskan, Magdalena M. Szewczyk, Zhengtian Yu, Mohammad S. Eram, Xiaobao Yang, Keith Schmidt, Xiao Luo, Miao Dai, Feng He, Irene Zang, Ying Lin, Steven Kennedy, Fengling Li, Elena Dobrovetsky, Aiping Dong, David Smil, Sun Joon Min, Melissa Landon, Jennifer Lin-Jones, Xi Ping HuangBryan L. Roth, Matthieu Schapira, Peter Atadja, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Peter J. Brown, Kehao Zhao, Jian Jin, Masoud Vedadi

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

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. High selectivity: The first PRMT3 chemical probe, SGC707, was discovered by structure-based optimization. SGC707 is a potent PRMT3 inhibitor with outstanding selectivity. The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies.

Original languageEnglish
Pages (from-to)5166-5170
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number17
DOIs
StatePublished - 20 Apr 2015

Keywords

  • X-ray diffraction
  • allosteric inhibition
  • chemical probes
  • enzyme inhibitors
  • histone methylation

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