Kaniskan, H. Uemit Szewczyk, Magdalena M. Yu, Zhengtian Eram, Mohammad S. Yang, Xiaobao Schmidt, Keith Luo, Xiao Dai, Miao He, Feng Zang, Irene Lin, Ying Kennedy, Steven Li, Fengling Dobrovetsky, Elena Dong, Aiping Smil, David Min, Sun-Joon Landon, Melissa Lin-Jones, Jennifer Huang, Xi-Ping Roth, Bryan L. Schapira, Matthieu Atadja, Peter Barsyte-Lovejoy, Dalia Arrowsmith, Cheryl H. Brown, Peter J. Zhao, Kehao Jin, Jian Vedadi, Masoud 2024-01-20T07:30:24Z 2024-01-20T07:30:24Z 2022-01-25 2015-04 1433-7851 https://pubs.kist.re.kr/handle/201004/125564 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 cellactive 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 (IC5 = 31 perpendicular to 2 nm, K-D = 53 perpendicular to 2 nm) with outstanding selectivity (selective against 31 other methyl-transferases 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. English John Wiley & Sons Ltd. A Potent, Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3) Article 10.1002/anie.201412154 1 Angewandte Chemie International Edition, v.54, no.17, pp.5166 - 5170 Angewandte Chemie International Edition 54 17 5166 5170 N scie scopus 000354190800033 2-s2.0-84927720612 Chemistry, Multidisciplinary Chemistry Article POLY(A)-BINDING PROTEIN IN-VITRO METHYLATION EXPANSIONS SUBSTRATE GENE VIVO allosteric inhibition chemical probes enzyme inhibitors histone methylation X-ray diffraction