Structural highlights
Publication Abstract from PubMedPRMT3 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: approximately 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. Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3).,Kaniskan HU, Eram MS, Zhao K, Szewczyk MM, Yang X, Schmidt K, Luo X, Xiao S, Dai M, He F, Zang I, Lin Y, Li F, Dobrovetsky E, Smil D, Min SJ, Lin-Jones J, Schapira M, Atadja P, Li E, Barsyte-Lovejoy D, Arrowsmith CH, Brown PJ, Liu F, Yu Z, Vedadi M, Jin J J Med Chem. 2018 Feb 8;61(3):1204-1217. doi: 10.1021/acs.jmedchem.7b01674. Epub, 2018 Jan 5. PMID:29244490[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
This page was last modified 05:43, 16 May 2018.