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

ABSTRACT: 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 (IC50 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.

SUBMITTER: Kaniskan HU

PROVIDER: S-EPMC5808361 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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

Kaniskan H Ümit HÜ Eram Mohammad S MS Zhao Kehao K Szewczyk Magdalena M MM Yang Xiaobao X Schmidt Keith K Luo Xiao X Xiao Sean S Dai Miao M He Feng F Zang Irene I Lin Ying Y Li Fengling F Dobrovetsky Elena E Smil David D Min Sun-Joon SJ Lin-Jones Jennifer J Schapira Matthieu M Atadja Peter P Li En E Barsyte-Lovejoy Dalia D Arrowsmith Cheryl H CH Brown Peter J PJ Liu Feng F Yu Zhengtian Z Vedadi Masoud M Jin Jian J

Journal of medicinal chemistry 20180105 3

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, an ...[more]

PMID: 29244490

Dataset Information

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

Publications

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

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