1 research outputs found
Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3)
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 <b>4</b>. 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 <b>4</b> and other highly potent (IC<sub>50</sub> values: ∼10–36 nM), selective, and cell-active allosteric
inhibitors of PRMT3 (compounds <b>29</b>, <b>30</b>, <b>36</b>, and <b>37</b>). In addition, we generated compounds
that are very close analogs of these potent inhibitors but displayed
drastically reduced potency as negative controls (compounds <b>49</b>–<b>51</b>). These inhibitors and negative
controls are valuable chemical tools for the biomedical community
to further investigate biological functions and disease associations
of PRMT3