70
3 In-Tether Chiral Center Induced Helical Peptide Modulators …
Table 3.1
Entry 2–11 were designed with different tether positions, tether type, and mutations at indicated positions. K
d was measured with fluorescence
polarization assays using FITC-labeled peptide R diastereomers with MDM2 and MDMX
Entry
Sequence
K
d (µM)
MDM
2
MDM
X
1
L
T
F
Q
H
Y
W
A
Q
L
T
S
NH
2
1.40
ND
2*(MeR)
L
T
F
C
H
Y
W
S
5 (Me)
Q
L
T
S
NH
2
0.16
0.53
3*(PhR)
L
T
F
C
H
Y
W
S
5 (Ph)
Q
L
T
S
NH
2
0.50
0.66
4R
L
T
F
Q
C
Y
W
A
S
5 (Me)
L
T
S
NH
2
0.56
ND
5R
L
T
F
Q
C
Y
W
A
S
5 (Ph)
L
T
S
NH
2
0.61
6R
L
C
F
Q
H
S
5 (Me)
W
A
Q
L
T
S
NH
2
>1.60
7R
F
C
H
Y
W
S
5 (Me)
Q
L
T
S
A
A
NH
2
>1.31
8R
L
T
F
C
H
Y
W
S
5 (Me)
Q
L
T
S
A
A
NH
2
1.06
9R
L
T
F
C
H
Y
W
S
5 (Ph)
Q
L
T
S
A
A
NH
2
>1.56
10R
L
T
F
Q
C
Y
W
A
S
5 (Me)
L
T
S
A
A
NH
2
>1.50
11R
L
T
F
Q
C
Y
W
A
S
5 (Ph)
L
T
S
A
A
NH
2
>4.14
12R
L
S
F
C
Q
Y
W
S
5 (Me)
Cba
L
S
P
NH
2
>1.36