9.3 Biological Relevance of Inhibitors and Current Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10 PRMT8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.2 Inhibitors: In Vitro and Cell-Based Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.3 Biological Relevance of Inhibitors and Current Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . 185
11 PRMT9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
12 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Abstract The methylation of arginine residues in numerous protein targets is a
post-translational modification that has gained increased interest in the scientific
community over the past two decades. Arginine methylation is performed by the
dedicated family of protein arginine methyltransferases and is known to be involved
in a plethora of cellular pathways and biochemical mechanisms in both healthy and
disease states. The development of inhibitors for these enzymes for use as biological
tools can lead to a more detailed understanding of the functions of the different
members of the PRMT family. In addition, a number of recent studies point towards
PRMTs as therapeutic targets for a number of diseases and the first clinical trials with
compounds inhibiting PRMTs are now underway. We here provide a broad overview of the current status of the inhibitors that have been developed against PRMTs
using both high-throughput screening and rational design approaches.
Keywords Activity, Inhibition, Methylation, Protein arginine N-methyltransferase,
Therapeutics
Abbreviations
aDMA
Asymmetrically dimethylated arginine
AdoHcy
S-adenosyl-L-homocysteine
AdoMet
S-adenosyl-L-methionine
Adox
Adenosine dialdehyde
AMI
Arginine methyltransferase inhibitor
AML
Acute myeloid leukaemia
CARM1
Coactivator-associated arginine methyltransferase
DNA
Deoxyribonucleic acid
EBV
Epstein-Barr virus
EC50
Half maximal effective concentration
GAR
Glycine-arginine rich
HEK293T Human embryonic kidney cell line
HepG2
Hepatocellular carcinoma cell line
HIV
Human immunodeficiency virus
IC 50
Half maximal inhibitory concentration
Ki
Inhibition constant
160
M. J. van Haren and N. I. Martin
10 PRMT8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.2 Inhibitors: In Vitro and Cell-Based Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
10.3 Biological Relevance of Inhibitors and Current Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . 185
11 PRMT9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
12 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Abstract The methylation of arginine residues in numerous protein targets is a
post-translational modification that has gained increased interest in the scientific
community over the past two decades. Arginine methylation is performed by the
dedicated family of protein arginine methyltransferases and is known to be involved
in a plethora of cellular pathways and biochemical mechanisms in both healthy and
disease states. The development of inhibitors for these enzymes for use as biological
tools can lead to a more detailed understanding of the functions of the different
members of the PRMT family. In addition, a number of recent studies point towards
PRMTs as therapeutic targets for a number of diseases and the first clinical trials with
compounds inhibiting PRMTs are now underway. We here provide a broad overview of the current status of the inhibitors that have been developed against PRMTs
using both high-throughput screening and rational design approaches.
Keywords Activity, Inhibition, Methylation, Protein arginine N-methyltransferase,
Therapeutics
Abbreviations
aDMA
Asymmetrically dimethylated arginine
AdoHcy
S-adenosyl-L-homocysteine
AdoMet
S-adenosyl-L-methionine
Adox
Adenosine dialdehyde
AMI
Arginine methyltransferase inhibitor
AML
Acute myeloid leukaemia
CARM1
Coactivator-associated arginine methyltransferase
DNA
Deoxyribonucleic acid
EBV
Epstein-Barr virus
EC50
Half maximal effective concentration
GAR
Glycine-arginine rich
HEK293T Human embryonic kidney cell line
HepG2
Hepatocellular carcinoma cell line
HIV
Human immunodeficiency virus
IC 50
Half maximal inhibitory concentration
Ki
Inhibition constant
160
M. J. van Haren and N. I. Martin