Biomedical Engineering Reference
In-Depth Information
COOH
O
O
O
H
N
H
N
N
OH
O
N
O
O
O
HN
N
NO
2
O
H
3
C
N
N
COOH
O
O
N
O
Cl
N
O
NH
N
Cl
Cl
N
N
I
N
I
O
COOH
O
O
N
CH
3
NH
2
O
Cl
Cl
Cl
nutlin-3
CH
3
Cl
N
HO
O
N
Cl
F
O
NH
O
CH
3
N
OH
NH
NH
OH
O
N
S
O
N
H
Cl
N
N
H
Cl
H
2
N
O
MI-63
CN
NH
OH
NH
N
O
NH
H
2
N
NH
F
NSC66811
COOH
Figure 3.54 Peptidomimetic inhibitors of the p53-HDM2 interaction
A variey of small-molecule inhibitors were discovered as a result of
screening programmes, some of them including preceding virtual screen-
ing (Figure 3.54). Among the first-reported small-molecule antagonists
were the tryptophyl-piperazine and the indole-substituted tryptophans
[379,380]. In the latter, the 2-phenoxy substituent was intended to target
the p53 Phe
19
binding site, and the substituted Trp to target the Trp
23
site.
The indole N1 substituent was intended to target the Leu
26
binding site.
A series of imidazoline compounds named nutlins were reported by
Hoffmann-La Roche [381]. They showed activity in the 100-300 nM
Search WWH ::
Custom Search