mechanisms through which the CBX7 aromatic cage closes around H3K27me3
suggested that replacement of the N-terminal benzoylglycine of UNC3567 with
less flexible structural moieties would enhance hydrogen bonding interactions with
CBX7 and facilitate closure of the chromodomain around the peptide. These SAR
studies resulted in UNC3866, which binds CBX7 and CBX4 (K D ¼ 97 nM) with
N +
O
H
N
CH3
CH3
O
N
H
O
H
N
CH3
O
N
N
H
H
H3C
CH3
CH3
O
H3C
OH
O
NH2
Ac-FALKme3S-NH2
N +
O
H
N
O
N
H
O
H
N
CH3
O
N
N
H
H
H3C
CH3
CH3
O
H3C
OH
O
NH2
OH
N +
O
H
N
O
N
H
O
H
N
CH3
O
N
N
H
H
H3C
CH3
CH3
O
OH
OH
MeOOC
CH3
CH3
N
O
H
N
CH3
CH3
O
N
H
O
H
N
CH3
O
N
N
H
H
O
OH
O
OMe
H3C
CH3
H3C
H3C
CH3
CH3
CH3
N
O
H
N
O
N
H
O
H
N
CH3
O
N
N
H
H
O
OH
O
NH2
UNC3567
UNC3866
UNC4991
O
H
N
N
NH
O
N
H
H
OH
H3C
O
H
N
OH
O
N
H
N +
O
H
N
CH3
CH3
O
N
H
O
H
N
CH3
O
N
H
O
H
N
NH2
HN
NH
O
N
H
OH
CH3
H3C
CH3
Ac-RGFALKme3STHG-NH2
H3C
O
FALKme3S analogue 11
FALKme3S analogue 64
N +
Any
O
H
N
Z
CH3
CH3
O
N
H
W
O
H
N
Y
CH3
O
N
X
N
H
H
H3C
CH3
CH3
O
H3C
OH
O
NH2
Ac-FALKme3S-NH2 aza-analogues
X=N Y=W=Z=CH
X=W=Z=CH Y=N
X=Y=Z=CH W=N
X=Y=W=CH Z=N
N
O
H
N
CH3
CH3
O
N
H
O
H
N
CH3
O
N
N
H
H
O
OH
O
OMe
H
N
O
CH3
H3C
Fig. 6 Peptide-based inhibitors of CBX7
352
G. Sbardella