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 cell- active 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 (IC50 = 31 ± 2 nm, KD = 53 ± 2 nm) with outstanding selectivity (selective against 31 other methyltransferases 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.
Micropatterned thin films of tailorable molecular materials with uniform, nanoscale cavities, such as 1, were prepared by soft lithographic methods. In this form the materials readily diffract visible light, and because the efficiency of diffraction is enhanced by sorption of guest molecules, the diffraction response can be used for signal transduction in chemical‐sensing applications.
] These authors contributed equally to this work.Supporting information for this article (including detailed synthetic procedures and compound characterization as well as methods for scaffold hopping, crystallization, structure determination, bio-chemical assays, SPR, ITC, PRMT3 InCELL Hunter assay, cellular PRMT3 assay, cell viability assay, and mouse PK studies) is available on the WWW under http://dx
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