Inhibitors of Protein Methyltransferases and Demethylases

Abstract

Post-translational modifications of histones by protein methyltransferases (PMTs) and histone demethylases (KDMs) play an important role in the regulation of gene expression and transcription and are implicated in cancer and many other diseases. Many of these enzymes also target various nonhistone proteins impacting numerous crucial biological pathways. Given their key biological functions and implications in human diseases, there has been a growing interest in assessing these enzymes as potential therapeutic targets. Consequently, discovering and developing inhibitors of these enzymes has become a very active and fast-growing research area over the past decade. In this review, we cover the discovery, characterization, and biological application of inhibitors of PMTs and KDMs with emphasis on key advancements in the field. We also discuss challenges, opportunities, and future directions in this emerging, exciting research field.

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

“…16 Dysregulation of GLP and G9a has been associated with numerous human diseases, including cancer, inflammatory diseases, and neurodegenerative disorder. 17–24 …”

Recent progress in developing selective inhibitors of protein methyltransferases

“…For example, PKMT inhibitors, such as BIX-01294, UNC0638, UNC0642 (G9a/GLP), EPZ005687, GSK126, EI1, UNC1999, EPZ-6438, CPI-1205 (EZH2/EZH1), EPZ004777, SGC0946, EPZ-5676 (DOT1L), AZ-505 and LLY507 (SMYD2) are valuable chemical tools for further understanding biological functions of the targeted enzymes and have already been widely used in evaluating the therapeutic potential of these proteins (Table 1). [9,10] In addition, highly potent, selective, substrate-competitive PRMT inhibitors including MS023 (type I PRMTs), TP-064 (CARM1), EPZ015666 (PRMT5) and EPZ020411 (PRMT6) have been accomplished, suggesting that the substrate-binding grooves of PRMTs can also be successfully targeted (Table 1). [9,12,13] The discovery of the first allosteric PRMT3 inhibitor and the development of the PRMT3 chemical probe SGC707 have demonstrated that the allosteric binding site of PRMT3 can be exploited to yield potent, selective, and cell-active inhibitors, opening the door for discovering allosteric inhibitors of other PRMTs (Table 1).…”

“…[9,10] In addition, highly potent, selective, substrate-competitive PRMT inhibitors including MS023 (type I PRMTs), TP-064 (CARM1), EPZ015666 (PRMT5) and EPZ020411 (PRMT6) have been accomplished, suggesting that the substrate-binding grooves of PRMTs can also be successfully targeted (Table 1). [9,12,13] The discovery of the first allosteric PRMT3 inhibitor and the development of the PRMT3 chemical probe SGC707 have demonstrated that the allosteric binding site of PRMT3 can be exploited to yield potent, selective, and cell-active inhibitors, opening the door for discovering allosteric inhibitors of other PRMTs (Table 1). [14] Moreover, the discovery of the covalent SETD8 inhibitor MS453 has demonstrated that cysteine residues in active sites of PMTs can be selectively targeted (Table 1).…”

“…[16–19] The design, synthesis and biological studies of many of these aforementioned inhibitors have already been discussed in detail in literature. [9,10] The following sections will focus only on the potent, selective small-molecule PMT inhibitors that are discovered very recently (indicated in bold type in Table 1). …”

“…[4–8] Therefore, the discovery of selective small-molecule inhibitors of protein methyltransferases (PMTs) has become a very active and fast growing research area (Figure 1). [9–11] In this review we focus on selective, small molecule inhibitors of PMTs that are discovered in last two years.…”