5.3.1 Targeting WDR5
As a common component of mammalian H3K4 methyltransferase complex, WDR5
is a major H3K4 methylation associated protein [209]. As a bridge between the
remainder units of the complex and MLL1, WDR5 bounds to a conserved arginine
containing motif of MLL1, called “WIN” or WDR5 interaction motif [205, 227,
228]. The interaction between MLL1 and WDR5 is critical for the integrity of
the MLL1 complex and, therefore, its HTM activity [229]. Knockdown of WDR5
affects the levels of global H3K4 methylation, especially decreases the level of
H3K4me1/3, and downregulates Hox gene expression in human cells [209]. So
disturbing the interaction of WDR5-MLL1 with antagonists to inhibit H3K4
methyltransferase activity can be a potential therapeutic strategy to treat leukemias
carrying MLL1 fusion proteins.
The discovery of the first inhibitor of MLL1-WDR5 interaction originated from
the identification of peptide Ac-ARA-NH 2 (Fig. 15) as the minimum MLL1-WIN
motif able to bind to WDR5 with high affinity [230]. Based on Ac-ARA-NH2, three
linear peptidomimetic inhibitors of MLL1-WDR5 PPI were identified (MM-101,
MM-102, and MM-103; estimated K i < 1 nM) by modification of the Ala residues
[231]. Then cyclic peptidomimetic MM-401 was designed by constraining conformation of the linear peptide MM-102 (Fig. 15) [229]. In a competitive FP
experiment, MM-401 showed an IC 50 value of 0.9 nM in disrupting the interaction
of WDR5 with MLL1. MM-401 was further demonstrated to specifically inhibit
the enzymatic activity of MLL1 (IC 50 ¼ 0.32 μM) by blocking the MLL1-WDR5
interaction and thus the assembly of the complex assembly. MM-401 is cytotoxic to
MLL-associated leukemic cells in an MLL1-mediated H3K4 methylation-dependent
manner by inducing cell cycle arrest, apoptosis, and myeloid differentiation, whereas
MM-102
HN
HN
O
H
N
HN
H 2 N
NH
O
CH 3
NH
O
H 3 C
CH 3
O
HN
HN
HN
O
H
N
HN
H 2 N
NH
O
O
NH
O
H 3 C
CH 3
O
CH 3
H 3 C
H 3 C
F
F
MM-401
HN
HN
HN
O
HN
HN
HN
NH
O
O
NH
O
H 3 C
CH 3
O
CH 3
H 3 C
CH 3
MM-589
CH 3
O
O
N
H
CH 3
HN
NH
H 2 N
O
H
N
O
N
CH 3
H 2 N
H
Ac-ARA-NH 2
Fig. 15 Peptide-based inhibitors of WDR5
376
G. Sbardella
As a common component of mammalian H3K4 methyltransferase complex, WDR5
is a major H3K4 methylation associated protein [209]. As a bridge between the
remainder units of the complex and MLL1, WDR5 bounds to a conserved arginine
containing motif of MLL1, called “WIN” or WDR5 interaction motif [205, 227,
228]. The interaction between MLL1 and WDR5 is critical for the integrity of
the MLL1 complex and, therefore, its HTM activity [229]. Knockdown of WDR5
affects the levels of global H3K4 methylation, especially decreases the level of
H3K4me1/3, and downregulates Hox gene expression in human cells [209]. So
disturbing the interaction of WDR5-MLL1 with antagonists to inhibit H3K4
methyltransferase activity can be a potential therapeutic strategy to treat leukemias
carrying MLL1 fusion proteins.
The discovery of the first inhibitor of MLL1-WDR5 interaction originated from
the identification of peptide Ac-ARA-NH 2 (Fig. 15) as the minimum MLL1-WIN
motif able to bind to WDR5 with high affinity [230]. Based on Ac-ARA-NH2, three
linear peptidomimetic inhibitors of MLL1-WDR5 PPI were identified (MM-101,
MM-102, and MM-103; estimated K i < 1 nM) by modification of the Ala residues
[231]. Then cyclic peptidomimetic MM-401 was designed by constraining conformation of the linear peptide MM-102 (Fig. 15) [229]. In a competitive FP
experiment, MM-401 showed an IC 50 value of 0.9 nM in disrupting the interaction
of WDR5 with MLL1. MM-401 was further demonstrated to specifically inhibit
the enzymatic activity of MLL1 (IC 50 ¼ 0.32 μM) by blocking the MLL1-WDR5
interaction and thus the assembly of the complex assembly. MM-401 is cytotoxic to
MLL-associated leukemic cells in an MLL1-mediated H3K4 methylation-dependent
manner by inducing cell cycle arrest, apoptosis, and myeloid differentiation, whereas
MM-102
HN
HN
O
H
N
HN
H 2 N
NH
O
CH 3
NH
O
H 3 C
CH 3
O
HN
HN
HN
O
H
N
HN
H 2 N
NH
O
O
NH
O
H 3 C
CH 3
O
CH 3
H 3 C
H 3 C
F
F
MM-401
HN
HN
HN
O
HN
HN
HN
NH
O
O
NH
O
H 3 C
CH 3
O
CH 3
H 3 C
CH 3
MM-589
CH 3
O
O
N
H
CH 3
HN
NH
H 2 N
O
H
N
O
N
CH 3
H 2 N
H
Ac-ARA-NH 2
Fig. 15 Peptide-based inhibitors of WDR5
376
G. Sbardella