to form a repressed E2F/pRb complex [170]. Homozygous deletion of L3MBTL3
was identified in human medulloblastoma [172], and, in general, reduced L3MBTL
expression may be relevant in certain subsets of myeloid leukemia [96, 173].
4.4.2 Small Molecules Targeting MBT Domains
The majority of small-molecule probes developed against MBT domains have
focused on L3MBTL1 and L3MBTL3 proteins. A crucial first step in targeting
methyllysine-binding proteins was the development and optimization of a broadly
applicable chemiluminescent AlphaScreen™ bead-based proximity assay capable
to identify small molecules that disrupt interactions between methylated histone
residues and the reader protein [174]. A preliminary screen identified two compounds, Cefsulodin and I-OME-Tyrphostin AG 538 (Fig. 11; IC50 ¼ 98 nM and
cefsulodine
I-OMe-tyrphostin AG538
N
+
H 2 N
O
S
N
OH
O
H
N
H
O
O
HO 3 S
HO
HO
O
CN
OCH 3
OH
I
NC
H 3 C
CH 3
HN CH 3
CH 3
O
S
N
H
CH 3
H 3 C
S N
H
O O
N
S N
H
O O
N
Br
N
N
H
O
N
Br
N
N
O
N
Br
N
H
O
N
H
N
O
N
HN
CH 3
VS Hit #1
VS Hit #2
VS Hit #13
peptide-like structure #6
UNC280
UNC669
pyrrolidine-containing sulfonamide #10
discontinued initial hits
Fig. 11 Initial hits and first generation probes for L3MBTL1 (compound numbering as in the
original papers) [175, 176]
Methyl-Readers and Inhibitors
365
was identified in human medulloblastoma [172], and, in general, reduced L3MBTL
expression may be relevant in certain subsets of myeloid leukemia [96, 173].
4.4.2 Small Molecules Targeting MBT Domains
The majority of small-molecule probes developed against MBT domains have
focused on L3MBTL1 and L3MBTL3 proteins. A crucial first step in targeting
methyllysine-binding proteins was the development and optimization of a broadly
applicable chemiluminescent AlphaScreen™ bead-based proximity assay capable
to identify small molecules that disrupt interactions between methylated histone
residues and the reader protein [174]. A preliminary screen identified two compounds, Cefsulodin and I-OME-Tyrphostin AG 538 (Fig. 11; IC50 ¼ 98 nM and
cefsulodine
I-OMe-tyrphostin AG538
N
+
H 2 N
O
S
N
OH
O
H
N
H
O
O
HO 3 S
HO
HO
O
CN
OCH 3
OH
I
NC
H 3 C
CH 3
HN CH 3
CH 3
O
S
N
H
CH 3
H 3 C
S N
H
O O
N
S N
H
O O
N
Br
N
N
H
O
N
Br
N
N
O
N
Br
N
H
O
N
H
N
O
N
HN
CH 3
VS Hit #1
VS Hit #2
VS Hit #13
peptide-like structure #6
UNC280
UNC669
pyrrolidine-containing sulfonamide #10
discontinued initial hits
Fig. 11 Initial hits and first generation probes for L3MBTL1 (compound numbering as in the
original papers) [175, 176]
Methyl-Readers and Inhibitors
365