compound displayed the reduction of tumor formation in vivo in zebrafish
xenografts [121].
2.3.4 Sirtuin-Rearranging Ligand2 as an Isoform-Selective Inhibitor
for SIRT2
Sirtuin-rearranging ligand2 (SirReal2) was identified by in vitro screening campaign
(compound 40 in Fig. 8) [122]. SirReal2 was highly isoform-selective compound
which exhibited the inhibition of SIRT2 with IC 50 value of 400 nM, and it showed
no activity toward SIRT3–5. SirReal2 displayed low inhibitory activities for SIRT1
(22% inhibition at 100 μM) and for SIRT6 (19% inhibition at 200 μM). The crystal
structure of SIRT2 with co-crystallized SirReal2 revealed that SirReal2 bound via
hydrophobic interactions into the extended nicotinamide moiety pocket of SIRT2
(Fig. 9) [122]. The extended pocket of nicotinamide moiety had been proposed from
a previous molecular modeling study [123].
Several aminothiazole derivatives were developed based on the SirReal2 compound, and they were also SIRT2 selective inhibitors [124, 125]. Interestingly, one
derivative (compound 41 in Fig. 8) was generated by combining aminothiazoles with
thalidomide; this compound displayed an IC 50 value of 250 nM for SIRT2 [126].
S
N
NH
S
O
N
N
CH 3
CH 3
SIRT1: weak
SIRT2: 400 nM
SIRT3: no
SIRT4: no
SIRT5: no
SIRT6 : weak
S
N
N
H
S
O
N
N
H 3 C
CH 3
O
N
N
N
NH
O
O
N
O
O
HN
O
O
SIRT1: >100 M
SIRT2: 250 nM
SIRT3: >100
NH
S
O
N
N
H 3 C
H 3 C
O
NH
O
S
2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivative (42)
SIRT1: > 300 nM
SIRT2: 42 nM
SIRT3: >300 nM
SirReal2 combined with thalidomide (41)
SirReal2 (40)
Fig. 8 The structures of SirReal2 and its derivatives and their IC 50 values
70
M. Rahnasto-Rilla et al.
xenografts [121].
2.3.4 Sirtuin-Rearranging Ligand2 as an Isoform-Selective Inhibitor
for SIRT2
Sirtuin-rearranging ligand2 (SirReal2) was identified by in vitro screening campaign
(compound 40 in Fig. 8) [122]. SirReal2 was highly isoform-selective compound
which exhibited the inhibition of SIRT2 with IC 50 value of 400 nM, and it showed
no activity toward SIRT3–5. SirReal2 displayed low inhibitory activities for SIRT1
(22% inhibition at 100 μM) and for SIRT6 (19% inhibition at 200 μM). The crystal
structure of SIRT2 with co-crystallized SirReal2 revealed that SirReal2 bound via
hydrophobic interactions into the extended nicotinamide moiety pocket of SIRT2
(Fig. 9) [122]. The extended pocket of nicotinamide moiety had been proposed from
a previous molecular modeling study [123].
Several aminothiazole derivatives were developed based on the SirReal2 compound, and they were also SIRT2 selective inhibitors [124, 125]. Interestingly, one
derivative (compound 41 in Fig. 8) was generated by combining aminothiazoles with
thalidomide; this compound displayed an IC 50 value of 250 nM for SIRT2 [126].
S
N
NH
S
O
N
N
CH 3
CH 3
SIRT1: weak
SIRT2: 400 nM
SIRT3: no
SIRT4: no
SIRT5: no
SIRT6 : weak
S
N
N
H
S
O
N
N
H 3 C
CH 3
O
N
N
N
NH
O
O
N
O
O
HN
O
O
SIRT1: >100 M
SIRT2: 250 nM
SIRT3: >100
NH
S
O
N
N
H 3 C
H 3 C
O
NH
O
S
2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivative (42)
SIRT1: > 300 nM
SIRT2: 42 nM
SIRT3: >300 nM
SirReal2 combined with thalidomide (41)
SirReal2 (40)
Fig. 8 The structures of SirReal2 and its derivatives and their IC 50 values
70
M. Rahnasto-Rilla et al.