(Adox, 4) is a known inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH)
which leads to a build-up of AdoHcy. Via this mechanism Adox is an indirect
methyltransferase inhibitor that can be used in cellular assays. Methylthioadenosine
(MTA, 5) is sometimes mentioned as a general methyltransferase inhibitor, but
recent publications show MTA is rather specific in inhibiting PRMTs (see
subchapter on PRMT5) [47–49].
2.2 Inhibitors: In Vitro and Cell-Based Activities
Recently, a more targeted general PRMT inhibitor was reported by Jin and
co-workers [50]. The compound, designated as MS023 (6, Fig. 3), inhibits all type
I PRMTs. Its design was based on the structures of other PRMT inhibitors specific
for PRMT4 and PRMT6 also containing an ethylenediamino group which was found
to function as an arginine mimetic. Building upon structure-activity relationship
(SAR) studies, MS023 was developed and, along with the negative control compound MS094 (lacking the ethylenediamino moiety), tested against a panel of
methyltransferases. The results showed potent inhibition of all type I PRMTs with
activities from 4 to 119 nM with no inhibition of type II and III PRMTs, lysine
methyltransferases, DNA methyltransferases, histone demethylases and methylreaders [50]. A co-crystal structure of MS023 bound to PRMT6 in the presence of
AdoHcy (Fig. 3) shows the interactions of the ethylenediamino group in the active
site where the arginine moiety would be expected to bind. Replacement of the
terminal amine with a hydroxyl group as in MS094 (7, Fig. 3) leads to complete
loss of inhibitory activity. The cellular assays performed with MS023 showed a
decrease in asymmetric dimethylation of histone H4R3 by PRMT1 with an IC 50
value of 9 nM and of H3R2 by PRMT6 with an IC 50 value of 56 nM. Also of note,
the decrease in cellular aDMA levels was accompanied by a measurable increase in
MMA and symmetrically dimethylated arginine (sDMA) levels. Interestingly, no
explanation has yet been provided for the striking selectivity observed for MS023 in
O
HO
OH
N
N
N
N
H 2 N
S
O
NH 3
O
AdoHcy (1)
sinefungin (3)
Aza-AdoMet (2)
O
HO
OH
N
N
N
N
H 2 N
O
NH 3
O
O
HO
OH
N
N
N
N
H 2 N
N
O
NH 3
O
NH 2
O
O
O
N
N
N
N
H 2 N
OH
Adox (4)
O
HO
OH
N
N
N
N
H 2 N
S
MTA (5)
Fig. 2 General methyltransferase inhibitors S-adenosyl-L-homocysteine (AdoHcy, 1), nitrogen
analogue Aza-AdoMet (2), bacterial compound sinefungin (3), indirect inhibitor adenosine
dialdehyde (Adox, 4) and methylthioadenosine (MTA, 5)
164
M. J. van Haren and N. I. Martin
which leads to a build-up of AdoHcy. Via this mechanism Adox is an indirect
methyltransferase inhibitor that can be used in cellular assays. Methylthioadenosine
(MTA, 5) is sometimes mentioned as a general methyltransferase inhibitor, but
recent publications show MTA is rather specific in inhibiting PRMTs (see
subchapter on PRMT5) [47–49].
2.2 Inhibitors: In Vitro and Cell-Based Activities
Recently, a more targeted general PRMT inhibitor was reported by Jin and
co-workers [50]. The compound, designated as MS023 (6, Fig. 3), inhibits all type
I PRMTs. Its design was based on the structures of other PRMT inhibitors specific
for PRMT4 and PRMT6 also containing an ethylenediamino group which was found
to function as an arginine mimetic. Building upon structure-activity relationship
(SAR) studies, MS023 was developed and, along with the negative control compound MS094 (lacking the ethylenediamino moiety), tested against a panel of
methyltransferases. The results showed potent inhibition of all type I PRMTs with
activities from 4 to 119 nM with no inhibition of type II and III PRMTs, lysine
methyltransferases, DNA methyltransferases, histone demethylases and methylreaders [50]. A co-crystal structure of MS023 bound to PRMT6 in the presence of
AdoHcy (Fig. 3) shows the interactions of the ethylenediamino group in the active
site where the arginine moiety would be expected to bind. Replacement of the
terminal amine with a hydroxyl group as in MS094 (7, Fig. 3) leads to complete
loss of inhibitory activity. The cellular assays performed with MS023 showed a
decrease in asymmetric dimethylation of histone H4R3 by PRMT1 with an IC 50
value of 9 nM and of H3R2 by PRMT6 with an IC 50 value of 56 nM. Also of note,
the decrease in cellular aDMA levels was accompanied by a measurable increase in
MMA and symmetrically dimethylated arginine (sDMA) levels. Interestingly, no
explanation has yet been provided for the striking selectivity observed for MS023 in
O
HO
OH
N
N
N
N
H 2 N
S
O
NH 3
O
AdoHcy (1)
sinefungin (3)
Aza-AdoMet (2)
O
HO
OH
N
N
N
N
H 2 N
O
NH 3
O
O
HO
OH
N
N
N
N
H 2 N
N
O
NH 3
O
NH 2
O
O
O
N
N
N
N
H 2 N
OH
Adox (4)
O
HO
OH
N
N
N
N
H 2 N
S
MTA (5)
Fig. 2 General methyltransferase inhibitors S-adenosyl-L-homocysteine (AdoHcy, 1), nitrogen
analogue Aza-AdoMet (2), bacterial compound sinefungin (3), indirect inhibitor adenosine
dialdehyde (Adox, 4) and methylthioadenosine (MTA, 5)
164
M. J. van Haren and N. I. Martin