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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kaniskan HÜ,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

doi

10.1021/acs.jmedchem.7b01674

subject

Has Abstract

pub_date

2018-02-08 00:00:00

pages

1204-1217

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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