(40, Fig. 9), a potent allosteric inhibitor of PRMT3 with an IC 50 of 31 nM and high
selectivity for PRMT3 over almost 300 other methyltransferase enzymes, including
PRMT1 and PRMT4–PRMT8 [112, 113]. SGC707 is cell-active and non-toxic,
except for high concentrations and long exposures. Initial PK data in mice show it
can be used in animal models. No disease relevant studies have yet been reported.
5.3 Biological Relevance of Inhibitors and Current Outlook
The nanomolar activity of SGC707 combined with its high selectivity provides a
strong tool for probing the biological role(s) of PRMT3. While links with human
disease are currently limited, its interaction with tumour suppressor DAL-1/4.1B
suggests PRMT3 as a potential target in breast cancer.
6 CARM1 (PRMT4)
6.1 Background
First identified as coactivator-associated arginine methyltransferase [12], CARM1 –
or PRMT4 – was the fourth PRMT to be found through its sequence homology with
PRMT1, PRMT2 and PRMT3. Unlike the other PRMTs, CARM1 doesn’t recognize
the GAR motif but prefers proline-, glycine- and methionine-rich (PGM) motifs
[114, 115]. CARM1 asymmetrically dimethylates histone residues H3R17, H3R26
and H3R42 [116–118] and a large number of nonhistone substrates, including
splicing factors, RNA-binding proteins, transcription factors, coactivators and itself
[114, 119, 120].
In a well-characterized example of crosstalk between post-translational modifications, the methylation of Arg17 in the histone H3-tail peptide is regulated by the
acetylation state of the neighbouring Lys18. Specifically, acetylation of Lys18
makes the H3 tail a better substrate for CARM1 [121]. Automethylation and
O-GlcNAcylation of CARM1 is also known to regulate substrate specificity
[122]. Upregulation of CARM1 is associated with a variety of diseases, including
breast [43, 123], colon [124, 125], prostate [124, 126] and liver [127] cancers.
Therefore, CARM1 has received increasing attention as a therapeutic target.
6.2 Inhibitors: In Vitro and Cell-Based Activities
Through a series of high-throughput screens and hit-to-lead SAR optimizations,
different pyrazole (40–42, 47 and CMPD-2 (43)), benzo[d]imidazole (48) and
indole-type (CMPD-1 (50) and 53) inhibitors were developed with IC 50 values as
PRMT Inhibitors
173
selectivity for PRMT3 over almost 300 other methyltransferase enzymes, including
PRMT1 and PRMT4–PRMT8 [112, 113]. SGC707 is cell-active and non-toxic,
except for high concentrations and long exposures. Initial PK data in mice show it
can be used in animal models. No disease relevant studies have yet been reported.
5.3 Biological Relevance of Inhibitors and Current Outlook
The nanomolar activity of SGC707 combined with its high selectivity provides a
strong tool for probing the biological role(s) of PRMT3. While links with human
disease are currently limited, its interaction with tumour suppressor DAL-1/4.1B
suggests PRMT3 as a potential target in breast cancer.
6 CARM1 (PRMT4)
6.1 Background
First identified as coactivator-associated arginine methyltransferase [12], CARM1 –
or PRMT4 – was the fourth PRMT to be found through its sequence homology with
PRMT1, PRMT2 and PRMT3. Unlike the other PRMTs, CARM1 doesn’t recognize
the GAR motif but prefers proline-, glycine- and methionine-rich (PGM) motifs
[114, 115]. CARM1 asymmetrically dimethylates histone residues H3R17, H3R26
and H3R42 [116–118] and a large number of nonhistone substrates, including
splicing factors, RNA-binding proteins, transcription factors, coactivators and itself
[114, 119, 120].
In a well-characterized example of crosstalk between post-translational modifications, the methylation of Arg17 in the histone H3-tail peptide is regulated by the
acetylation state of the neighbouring Lys18. Specifically, acetylation of Lys18
makes the H3 tail a better substrate for CARM1 [121]. Automethylation and
O-GlcNAcylation of CARM1 is also known to regulate substrate specificity
[122]. Upregulation of CARM1 is associated with a variety of diseases, including
breast [43, 123], colon [124, 125], prostate [124, 126] and liver [127] cancers.
Therefore, CARM1 has received increasing attention as a therapeutic target.
6.2 Inhibitors: In Vitro and Cell-Based Activities
Through a series of high-throughput screens and hit-to-lead SAR optimizations,
different pyrazole (40–42, 47 and CMPD-2 (43)), benzo[d]imidazole (48) and
indole-type (CMPD-1 (50) and 53) inhibitors were developed with IC 50 values as
PRMT Inhibitors
173