and selective (18-, 30- and >42-fold over PRMT5, PRMT6 and PRMT4, respectively) inhibitor of PRMT1. Interestingly, furamidine was found to inhibit proliferation in leukaemia cell lines with higher sensitivity in cell lines derived from Down’s
syndrome patients and individuals diagnosed with mixed lineage leukaemia (MLL)
[92]. Subsequent investigation of spacer length in diamidines revealed decamidine
(32), bearing a 10-carbon spacer, to be a slightly more active (13 μM IC 50 compared
to 22 μM found for furamidine) but less specific PRMT1 inhibitor compared to
furamidine. No additional analogues containing longer spacers were reported so the
optimal spacing has yet to be confirmed [93]. The same group also investigated
cyanine dyes as PRMT inhibitors and found compound 33 (Fig. 7) as an active hit
with IC 50 values of 0.61–1.74 μM against PRMT1, PRMT3, PRMT4, PRMT5,
PRMT6 and PRMT8. This study also revealed compound 34 as a partially selective
hit with an IC 50 of 3.38 μM against PRMT1 with 6-, 10- and 25-fold selectivity over
PRMT4, PRMT5 and PRMT8, respectively, but with no selectivity for PRMT3 or
PRMT6 [94, 95]. Compound 34 was also tested in three different leukaemia cell
lines and showed significant cell growth inhibition at 100–200 nM.
Also recently, an SAR study was reported by Yang and co-workers based upon a
nitropyrimidine hit from a screening campaign [96]. This work showed that the
amidine moiety was important for PRMT1 inhibition with modelling studies
suggesting that it binds with the double E-loop of the enzyme. The optimized
nitropyrimidine compound 35 (Fig. 7) showed an IC 50 of 2.0 μM for PRMT1 with
fivefold selectivity over PRMT4 and no activity against PRMT5 and PRMT6.
Cellular assays revealed low micromolar IC 50 activity against colon cancer
(4.4 μM), bladder cancer (13.1 μM) and neuroblastoma (11.4 μM) tumour cell
lines [96]. In a parallel study, the same group reported nitropyrimidine-diamidine
compound SKLB-639 (36, Fig. 7) with similar activity against PRMT1 (2.4 μM) and
selectivities of 15-fold over PRMT3, 30-fold over PRMT4 and no activity against
HN
H 2 N
O
NH 2
NH
H 2 N
HN
NH 2
NH
stilbamidine (30)
furamidine (31)
O
HN
H 2 N
O
H 2 N
NH
decamidine (32)
N
Br
Br
N
Br
34
N
N
Br
33
N
N
NO 2
N
H
N
H
NH
NH 2
N
N
N
NO 2
N
H
N
H
NH
NH 2
H 2 N
NH
35
SKLB-639 (36)
Fig. 7 Diamidines 30–32, carbocyanine dyes 33–34 and nitropyrimidines 35–36 as inhibitors of
PRMT1
PRMT Inhibitors
169
syndrome patients and individuals diagnosed with mixed lineage leukaemia (MLL)
[92]. Subsequent investigation of spacer length in diamidines revealed decamidine
(32), bearing a 10-carbon spacer, to be a slightly more active (13 μM IC 50 compared
to 22 μM found for furamidine) but less specific PRMT1 inhibitor compared to
furamidine. No additional analogues containing longer spacers were reported so the
optimal spacing has yet to be confirmed [93]. The same group also investigated
cyanine dyes as PRMT inhibitors and found compound 33 (Fig. 7) as an active hit
with IC 50 values of 0.61–1.74 μM against PRMT1, PRMT3, PRMT4, PRMT5,
PRMT6 and PRMT8. This study also revealed compound 34 as a partially selective
hit with an IC 50 of 3.38 μM against PRMT1 with 6-, 10- and 25-fold selectivity over
PRMT4, PRMT5 and PRMT8, respectively, but with no selectivity for PRMT3 or
PRMT6 [94, 95]. Compound 34 was also tested in three different leukaemia cell
lines and showed significant cell growth inhibition at 100–200 nM.
Also recently, an SAR study was reported by Yang and co-workers based upon a
nitropyrimidine hit from a screening campaign [96]. This work showed that the
amidine moiety was important for PRMT1 inhibition with modelling studies
suggesting that it binds with the double E-loop of the enzyme. The optimized
nitropyrimidine compound 35 (Fig. 7) showed an IC 50 of 2.0 μM for PRMT1 with
fivefold selectivity over PRMT4 and no activity against PRMT5 and PRMT6.
Cellular assays revealed low micromolar IC 50 activity against colon cancer
(4.4 μM), bladder cancer (13.1 μM) and neuroblastoma (11.4 μM) tumour cell
lines [96]. In a parallel study, the same group reported nitropyrimidine-diamidine
compound SKLB-639 (36, Fig. 7) with similar activity against PRMT1 (2.4 μM) and
selectivities of 15-fold over PRMT3, 30-fold over PRMT4 and no activity against
HN
H 2 N
O
NH 2
NH
H 2 N
HN
NH 2
NH
stilbamidine (30)
furamidine (31)
O
HN
H 2 N
O
H 2 N
NH
decamidine (32)
N
Br
Br
N
Br
34
N
N
Br
33
N
N
NO 2
N
H
N
H
NH
NH 2
N
N
N
NO 2
N
H
N
H
NH
NH 2
H 2 N
NH
35
SKLB-639 (36)
Fig. 7 Diamidines 30–32, carbocyanine dyes 33–34 and nitropyrimidines 35–36 as inhibitors of
PRMT1
PRMT Inhibitors
169