10.3 Biological Relevance of Inhibitors and Current Outlook
Although relatively little is known about the roles of PRMT8 in both healthy and
disease states, recent publications suggest its potential as a therapeutic target. In
order to study these in greater detail, the development of specific inhibitors against
PRMT8 will be necessary.
11 PRMT9
The most recently added member of the PRMT family, PRMT9, took longer to
identify due to its low sequence similarity to other PRMTs [17, 18]. Initially
described in the literature as Fbox Only Protein 11 (FBXO11), PRMT9 is the second
type II PRMT after PRMT5 and is found to localize mainly in the cytoplasm
[18, 197]. Recently, spliceosome-associated protein SAP145 was identified as a
substrate for PRMT9 [197]. sDMA methylation of SAP145 results in a Tudor
domain-binding site for the survival of motor neuron (SMN) protein, thereby
regulating alternative splicing.
Recently, the preferred substrate recognition motif of PRMT9 was described as
R-F-(K/R/F)-(R/W)-R-(M/F)-P-X-P [198], which may facilitate the identification of
new PRMT9 substrates. Interestingly, however, the only substrate identified to date
(spliceosome-associated protein 145 (SAP145)) does not bear this motif
(CFKRKYL). Currently, a very limited number of studies focused on PRMT9
have been reported, and much work is needed to elucidate the roles played by
PRMT9 in both healthy and disease states.
12 Conclusions
The protein arginine N-methyltransferases play crucial roles in a wide range of
biological processes associated with both human health and disease. Their functions
concentrate on gene regulation, RNA transcription, splicing processes and DNA
repair. Not surprisingly, the dysregulation of PRMTs has been shown to contribute
to a variety of diseases, including many different cancers. As a result, the development of PRMT inhibitors has also received increasing attention over the past decade.
Comparing different studies focused on inhibiting the same PRMT can prove
challenging as different assay methods can result in different IC 50 values for the
same compound. Furthermore, many factors are involved in obtaining a reliable
measure of an inhibitor’s potency, including substrate and enzyme concentrations,
the reference compounds used, signal readout and many other variable assay-specific
conditions. In addition, PRMT inhibitor specificity is rarely tested in the context of a
large panel of methyltransferases.
PRMT Inhibitors
185
Although relatively little is known about the roles of PRMT8 in both healthy and
disease states, recent publications suggest its potential as a therapeutic target. In
order to study these in greater detail, the development of specific inhibitors against
PRMT8 will be necessary.
11 PRMT9
The most recently added member of the PRMT family, PRMT9, took longer to
identify due to its low sequence similarity to other PRMTs [17, 18]. Initially
described in the literature as Fbox Only Protein 11 (FBXO11), PRMT9 is the second
type II PRMT after PRMT5 and is found to localize mainly in the cytoplasm
[18, 197]. Recently, spliceosome-associated protein SAP145 was identified as a
substrate for PRMT9 [197]. sDMA methylation of SAP145 results in a Tudor
domain-binding site for the survival of motor neuron (SMN) protein, thereby
regulating alternative splicing.
Recently, the preferred substrate recognition motif of PRMT9 was described as
R-F-(K/R/F)-(R/W)-R-(M/F)-P-X-P [198], which may facilitate the identification of
new PRMT9 substrates. Interestingly, however, the only substrate identified to date
(spliceosome-associated protein 145 (SAP145)) does not bear this motif
(CFKRKYL). Currently, a very limited number of studies focused on PRMT9
have been reported, and much work is needed to elucidate the roles played by
PRMT9 in both healthy and disease states.
12 Conclusions
The protein arginine N-methyltransferases play crucial roles in a wide range of
biological processes associated with both human health and disease. Their functions
concentrate on gene regulation, RNA transcription, splicing processes and DNA
repair. Not surprisingly, the dysregulation of PRMTs has been shown to contribute
to a variety of diseases, including many different cancers. As a result, the development of PRMT inhibitors has also received increasing attention over the past decade.
Comparing different studies focused on inhibiting the same PRMT can prove
challenging as different assay methods can result in different IC 50 values for the
same compound. Furthermore, many factors are involved in obtaining a reliable
measure of an inhibitor’s potency, including substrate and enzyme concentrations,
the reference compounds used, signal readout and many other variable assay-specific
conditions. In addition, PRMT inhibitor specificity is rarely tested in the context of a
large panel of methyltransferases.
PRMT Inhibitors
185