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Mounting evidence suggests that protein methyltransferases (PMTs), which catalyze methylation of histones as well as non-histone proteins, play a crucial role in diverse biological pathways and human diseases. In particular, PMTs have been recognized as major players in regulating gene expression and chromatin state. There has been an increasingly growing interest in these enzymes as potential therapeutic targets and over the past two years tremendous progress has been made in the discovery of selective, small molecule inhibitors of protein lysine and arginine methyltransferases. Inhibitors of PMTs have been used extensively in oncology studies as tool compounds, and inhibitors of EZH2, DOT1L and PRMT5 are currently in clinical trials. [ABSTRACT FROM AUTHOR]

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 n M, KD=53±2 n M) 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. [ABSTRACT FROM AUTHOR]

Mountingevidence suggests that protein methyltransferases (PMTs),which catalyze methylation of histone and nonhistone proteins, playa crucial role in diverse biological processes and human diseases.In particular, PMTs have been recognized as major players in regulatinggene expression and chromatin state. PMTs are divided into two categories:protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases(PRMTs). There has been a steadily growing interest in these enzymesas potential therapeutic targets and therefore discovery of PMT inhibitorshas also been pursued increasingly over the past decade. Here, wepresent a perspective on selective, small-molecule inhibitors of PMTswith an emphasis on their discovery, characterization, and applicabilityas chemical tools for deciphering the target PMTs’ physiologicalfunctions and involvement in human diseases. We highlight the currentstate of PMT inhibitors and discuss future directions and opportunitiesfor PMT inhibitor discovery. [ABSTRACT FROM AUTHOR]

EZH2 or EZH1 (enhancer of zeste homologue 2 or 1) is the catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 lysine 27 (H3K27). PRC2 hyperactivity and/or hypertrimethylation of H3K27 are associated with numerous human cancers, therefore inhibition of PRC2 complex has emerged as a promising therapeutic approach. Recent studies have shown that EZH2 and EZH1 are not functionally redundant and inhibition of both EZH2 and EZH1 is necessary to block the progression of certain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias. Despite the significant advances in discovery of EZH2 inhibitors, there has not been a systematic structure-activity relationship (SAR) study to investigate the selectivity between EZH2 and EZH1 inhibition. Here, we report our SAR studies that focus on modifications to various regions of the EZH2/1 inhibitor UNC1999 (5) to investigate the impact of the structural changes on EZH2 and EZH1 inhibition and selectivity. [ABSTRACT FROM AUTHOR]