have, however, become the source of some debate as the results could not be
reproduced by other groups [21–26]. Recently, other members of the Jumonjidomain containing lysine demethylases (KDM4E and KDM5C) were also shown
to demethylate arginines in histones in vitro, suggesting the process is indeed
dynamic [27]. However, at this point in time, in vivo proof for the presence of
arginine-specific demethylases is still lacking. In this regard, the only certain way to
control arginine methylation remains via inhibition of the PRMTs.
A great number of protein substrates have been identified for the different
PRMTs, ranging from general substrates to others that are only acted upon by one
specific PRMT [28–30]. Arginine methylation by PRMTs is involved in many
cellular processes, including RNA processing, gene transcription, signal transduction and DNA repair [31, 32]. In terms of their biological roles, the PRMTs have
little redundancy as indicated by the dramatic phenotypes observed in knockout
mice [31]. A growing body of evidence implicates dysregulated arginine methylation in a variety of diseases, including numerous cancers [32], cardiovascular [33],
pulmonary [34–36] and viral diseases [37, 38]. In an attempt to address the connection between aberrant PRMT activity and human disease, the Bedford group
published the first report describing PRMT inhibitors in 2004 [39]. Since this
time, the number of publications describing new, more potent and selective PRMT
inhibitors has steadily increased.
The recent interest in the field of PRMTs has led to growing amounts of data
along with reviews describing the progress made in different areas of research [40–
46]. We here provide an overview on the current status of the development of
compounds aimed at inhibiting PRMTs. Starting with a brief summary of general
methyltransferase inhibitors, we then address the development of inhibitors specific
for each of the nine PRMTs, followed by a brief discussion on their biological
relevance. In cases where a compound has inhibitory activity against more than one
PRMT, it will be discussed in the context of the enzyme that is inhibited with the
highest activity and selectivity.
2 Nonspecific Protein Methyltransferase Inhibitors
2.1 Background
The enzymatic reaction performed by PRMTs and other methyltransferases using
AdoMet as the methyl donor is self-regulating due to the inhibitory properties of
cofactor byproduct, AdoHcy (1). Structurally similar compounds include
Aza-AdoMet (2), where the sulphur of AdoMet is replaced by a nitrogen atom,
and the bacterially produced natural product sinefungin (3, Fig. 2). These compounds are known to inhibit all AdoMet-dependent methyltransferases by competition with AdoMet. It is due to this mechanism of action that the AdoMet analogues
lack specificity of inhibition. Therefore, the primary use of these analogues is as
reference inhibitors in both biochemical and cellular assays. Adenosine dialdehyde
PRMT Inhibitors
163
reproduced by other groups [21–26]. Recently, other members of the Jumonjidomain containing lysine demethylases (KDM4E and KDM5C) were also shown
to demethylate arginines in histones in vitro, suggesting the process is indeed
dynamic [27]. However, at this point in time, in vivo proof for the presence of
arginine-specific demethylases is still lacking. In this regard, the only certain way to
control arginine methylation remains via inhibition of the PRMTs.
A great number of protein substrates have been identified for the different
PRMTs, ranging from general substrates to others that are only acted upon by one
specific PRMT [28–30]. Arginine methylation by PRMTs is involved in many
cellular processes, including RNA processing, gene transcription, signal transduction and DNA repair [31, 32]. In terms of their biological roles, the PRMTs have
little redundancy as indicated by the dramatic phenotypes observed in knockout
mice [31]. A growing body of evidence implicates dysregulated arginine methylation in a variety of diseases, including numerous cancers [32], cardiovascular [33],
pulmonary [34–36] and viral diseases [37, 38]. In an attempt to address the connection between aberrant PRMT activity and human disease, the Bedford group
published the first report describing PRMT inhibitors in 2004 [39]. Since this
time, the number of publications describing new, more potent and selective PRMT
inhibitors has steadily increased.
The recent interest in the field of PRMTs has led to growing amounts of data
along with reviews describing the progress made in different areas of research [40–
46]. We here provide an overview on the current status of the development of
compounds aimed at inhibiting PRMTs. Starting with a brief summary of general
methyltransferase inhibitors, we then address the development of inhibitors specific
for each of the nine PRMTs, followed by a brief discussion on their biological
relevance. In cases where a compound has inhibitory activity against more than one
PRMT, it will be discussed in the context of the enzyme that is inhibited with the
highest activity and selectivity.
2 Nonspecific Protein Methyltransferase Inhibitors
2.1 Background
The enzymatic reaction performed by PRMTs and other methyltransferases using
AdoMet as the methyl donor is self-regulating due to the inhibitory properties of
cofactor byproduct, AdoHcy (1). Structurally similar compounds include
Aza-AdoMet (2), where the sulphur of AdoMet is replaced by a nitrogen atom,
and the bacterially produced natural product sinefungin (3, Fig. 2). These compounds are known to inhibit all AdoMet-dependent methyltransferases by competition with AdoMet. It is due to this mechanism of action that the AdoMet analogues
lack specificity of inhibition. Therefore, the primary use of these analogues is as
reference inhibitors in both biochemical and cellular assays. Adenosine dialdehyde
PRMT Inhibitors
163