gene transcription, nuclear transport, DNA repair and RNA processing, respectively
[32, 56]. PRMT1 is overexpressed in breast [53, 57], prostate [58], lung [59], colon
[60, 61], head and neck [62] and bladder cancer [63] and in leukaemia [32, 64,
65]. It is further involved in a number of other serious conditions ranging from
pulmonary disease [35, 66], cardiovascular disease [33] and diabetes [67] to cocaine
addiction [68].
3.2 Inhibitors: In Vitro and Cell-Based Activities
The first report on the development of PRMT inhibitors was published in 2004,
indicating the relative infancy of the field. A screening campaign resulted in the
identification of arginine methyltransferase inhibitors AMI-1 (8) and AMI-6 (9,
Fig. 4) with IC 50 values against PRMT1 of 8.8 and 5.1 μM, respectively
[39]. Small molecules based on AMI scaffolds, including AMI-5 (10, Fig. 4), were
studied via docking and binding studies [69], and a follow-up study with simplified
AMI-5 analogues showed inhibitory effects on different methyltransferases, including PRMT1 and PRMT4 and lysine methyltransferase SET7 (SET domain
containing protein) [70]. For several active compounds, cellular activity in human
leukaemia U937 cell lines was found with specific effects on cell cycle arrest,
apoptosis and granulocyte differentiation [70].
Follow-up studies revealed analogues of the AMI series, including naphthyl-sulfo
derivatives, such as compound NS-1 (11, Fig. 4), [71] and pharmacophore-based
small molecule inhibitors, like analogue A36 (12, Fig. 4), both of which exhibit IC 50
values in the low μM range [72]. Interestingly, it was later discovered that the
mechanism of action of these inhibitors is not by interaction with the PRMT but
rather with the histone H4 substrate and other glycine- and arginine-rich (GAR)
substrates, explaining – at least in part – the observed (lack of) specificities for these
compounds. Inspired by the findings of the AMI compounds, Mowen and
co-workers combined structural features of the different AMIs to generate new
OH
O 3 S
Na
N
H
N
H
O
OH
SO 3 Na
AMI-1 (8)
H
N
H
N
O
O
O
OH
HO
A36 (12)
O
CO 2 H
H
N
N
N
N
O
HO
Cl
Cl
AMI-6 (9)
OH
O 3 S
N
H
N
H
O
OH
SO 3
N
N
N
N
HN
O
NS-1 (11)
Na
Na
O
HO 2 C
O
HO
Br
Br
Br
Br
AMI-5 (10)
NH
HO
N
S
N
N
N
N
O
O
O
O
Cl
Cl
13
Fig. 4 PRMT1 inhibitors 8–13 interacting with the histone H4 and glycine-arginine-rich (GAR)
substrates
166
M. J. van Haren and N. I. Martin
[32, 56]. PRMT1 is overexpressed in breast [53, 57], prostate [58], lung [59], colon
[60, 61], head and neck [62] and bladder cancer [63] and in leukaemia [32, 64,
65]. It is further involved in a number of other serious conditions ranging from
pulmonary disease [35, 66], cardiovascular disease [33] and diabetes [67] to cocaine
addiction [68].
3.2 Inhibitors: In Vitro and Cell-Based Activities
The first report on the development of PRMT inhibitors was published in 2004,
indicating the relative infancy of the field. A screening campaign resulted in the
identification of arginine methyltransferase inhibitors AMI-1 (8) and AMI-6 (9,
Fig. 4) with IC 50 values against PRMT1 of 8.8 and 5.1 μM, respectively
[39]. Small molecules based on AMI scaffolds, including AMI-5 (10, Fig. 4), were
studied via docking and binding studies [69], and a follow-up study with simplified
AMI-5 analogues showed inhibitory effects on different methyltransferases, including PRMT1 and PRMT4 and lysine methyltransferase SET7 (SET domain
containing protein) [70]. For several active compounds, cellular activity in human
leukaemia U937 cell lines was found with specific effects on cell cycle arrest,
apoptosis and granulocyte differentiation [70].
Follow-up studies revealed analogues of the AMI series, including naphthyl-sulfo
derivatives, such as compound NS-1 (11, Fig. 4), [71] and pharmacophore-based
small molecule inhibitors, like analogue A36 (12, Fig. 4), both of which exhibit IC 50
values in the low μM range [72]. Interestingly, it was later discovered that the
mechanism of action of these inhibitors is not by interaction with the PRMT but
rather with the histone H4 substrate and other glycine- and arginine-rich (GAR)
substrates, explaining – at least in part – the observed (lack of) specificities for these
compounds. Inspired by the findings of the AMI compounds, Mowen and
co-workers combined structural features of the different AMIs to generate new
OH
O 3 S
Na
N
H
N
H
O
OH
SO 3 Na
AMI-1 (8)
H
N
H
N
O
O
O
OH
HO
A36 (12)
O
CO 2 H
H
N
N
N
N
O
HO
Cl
Cl
AMI-6 (9)
OH
O 3 S
N
H
N
H
O
OH
SO 3
N
N
N
N
HN
O
NS-1 (11)
Na
Na
O
HO 2 C
O
HO
Br
Br
Br
Br
AMI-5 (10)
NH
HO
N
S
N
N
N
N
O
O
O
O
Cl
Cl
13
Fig. 4 PRMT1 inhibitors 8–13 interacting with the histone H4 and glycine-arginine-rich (GAR)
substrates
166
M. J. van Haren and N. I. Martin