Small Molecule Inhibitors of Protein Arginine Methyltransferases

Abstract

Introduction Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery. Areas covered The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed. Expert opinion Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.

Protein Arginine Methyltransferase Product Specificity Is Mediated by Distinct Active-site Architectures

“…One of the major issues in this field, however, has been the promiscuity of many PRMT inhibitors derived from small molecule library screening (37). Approaches based on finding bisubstrate analogs that mimic the cofactor and the substrate arginine have the disadvantages of promiscuity and additionally, due to their highly charged nature, limited bioavailability precluding their administration as oral drugs (37).…”

“…One of the major issues in this field, however, has been the promiscuity of many PRMT inhibitors derived from small molecule library screening (37). Approaches based on finding bisubstrate analogs that mimic the cofactor and the substrate arginine have the disadvantages of promiscuity and additionally, due to their highly charged nature, limited bioavailability precluding their administration as oral drugs (37). In light of such obstacles in the development of small molecule inhibitors of PRMTs involved in various diseases, it is our hope that our model will facilitate the rational design of specific and potent PRMT inhibitors by providing detailed insight into the distinct active-site architectures of the three types of PRMTs.…”

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

“…For instance, type 2 fibers in Duchenne muscular dystrophy (DMD) patients are the first myofibers to degenerate and die, whereas type 1 fibers are more resistant to the dystrophic pathology (7,8). Similarly, myotonic dystrophy type 2 (DM2) patients demonstrate preferential type 2 fiber atrophy (9).…”

“…PRMTs are a family of enzymes that catalyze the methylation of arginine residues on target proteins (8,9). In turn, the stability, localization and activity of these marked proteins are altered.…”

Identification of Novel Inhibitors against Coactivator Associated Arginine Methyltransferase 1 Based on Virtual Screening and Biological Assays

“…To date, a number of CARM1 inhibitors have been reported [19–27] (see Figure S1 in Supplementary Material available online at http://dx.doi.org/10.1155/2016/7086390). According to the chemical structures, these inhibitors can be divided into several categories: (i) 3,5-bis(bromohydroxybenzylidene) piperidin-4-one inhibitors (compounds 1-2 in Figure S1), (ii) pyrazole inhibitors (compounds 3–10 in Figure S1), (iii) benzo[ d ]imidazole inhibitors (compounds 11–13 in Figure S1), and (iv) other inhibitors (compounds 14-15 in Figure S1) [28]. However, the majority of these inhibitors are lacking selectivity and drug-likeness; thus turning these inhibitors into therapeutically useful compounds is challenging.…”