Structure-based design and synthesis of small molecular inhibitors disturbing the interaction of MLL1-WDR5

Article abstract of DOI:10.1016/j.ejmech.2016.04.032

MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 protein-protein interaction (PPI) to inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute leukemia. WDR5-47 (IC₅₀ = 0.3 μM) was defined as a potent small molecule to disturb the interaction of MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to block MLL1-WDR5 PPI. Especially, compound 23 (IC₅₀ = 104 nM) was the most potent small molecular, and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds with docking study, which may stimulate more potent compounds.

Full text of DOI:10.1016/j.ejmech.2016.04.032

European Journal of Medicinal Chemistry 118 (2016) 1e8
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Structure-based design and synthesis of small molecular inhibitors
disturbing the interaction of MLL1-WDR5
,
,
,
b
,
,
, b
Dong-Dong Li a b, Wei-Lin Chen a b, Xiao-Li Xu a c, Fen Jiang a b, Lei Wang a
,
Yi-Yue Xie a b, Xiao-Jin Zhang a d, Xiao-Ke Guo a c, Qi-Dong You a
,
,
,
b
,
,
b,
, b, **
, b, c, *
Hao-Peng Sun a
a Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
d Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
MLL1 complex catalyzes the methylation of H3K4, and plays important roles in the development of acute
leukemia harboring MLL fusion proteins. Targeting MLL1-WDR5 proteineprotein interaction (PPI) to
inhibit the activity of histone methyltransferase of MLL1 complex is a novel strategy for treating of acute
Received 22 July 2015
Received in revised form
7 March 2016
Accepted 11 April 2016
Available online 13 April 2016
leukemia. WDR5-47 (IC50 ¼ 0.3
mM) was defined as a potent small molecule to disturb the interaction of
MLL1-WDR5. Here, we described structure-based design and synthesis of small molecular inhibitors to
block MLL1-WDR5 PPI. Especially, compound 23 (IC50 ¼ 104 nM) was the most potent small molecular,
and about 3-times more potent than WDR5-47. We also discussed the SAR of these series of compounds
with docking study, which may stimulate more potent compounds.
Keywords:
Histone methyltransfreases
MLL1-WDR5 interaction
Small molecular inhibitors
Leukemia
© 2016 Elsevier Masson SAS. All rights reserved.
1. Introduction
frame with different partner proteins to create oncogenic proteins
or MLL fusion proteins (MLL FPs), such as MLL-AF4, MLL-AF9, MLL-
Histone methyltransfreases (HTMs) are key enzymes that post-
translationally methylate histones and are required for the epige-
netic maintenance of transcriptionally active forms of chromatin in
eukaryotes [1,2]. MLL1(Mixed Lineage Leukemia 1), an important
member of histone 3 lysine 4 (H3K4) HTM, is capable of catalyzing
mono-, di-, and tri-methylation of H3K4 through its evolutionarily
conserved Su(var)3e9 enhancerof-zeste trithorax (SET) domain,
and plays vital rules in sustaining the express of Hox and Meis gene
in normal hematopoiesis [3,4]. H3K4me2/3 marks are most highly
correlated with Hox gene activation in vivo [5].
ENL, which contain only the amino-terminus of MLL1 protein [7].
H3K4me2/3 promotes gene activation by acting as a docking site for
PHD finger of wild type MLL1 in regulating normal hematopoiesis.
In leukemogenesis, MLL FPs are dependent on wild type MLL1
binding for recruitment to Hox gene to result, while MLL fusion
proteins lose the C-terminal SET domains [8].
MLL1 itself has extremely low monomethylate H3K4 activity. To
achieve maximal HTM activity, MLL1 was in complex with a
number of regulatory subunits, including WDR5, Ash2L, RBBP5, and
DPY30 [9,10]. Especially, WDR5 as a common component of
mammalian H3K4 methyltransferase complex, is a major H3K4
methylation associated protein [11]. 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 [12e14]. The interaction between MLL1
and WDR5 is critical for the integrity of the MLL1 complex and,
therefore, its HTM activity [15,16]. 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 [11]. So disturbing the interaction of WDR5-MLL1 with
Dysregulation of MLL1 is associated with many cancers and
developmental disorders of human such as acute lymphoid leu-
kemia (ALL) and acute myeloid leukemia (AML) [6]. MLL1 fuses in
* Corresponding author. State Key Laboratory of Natural Medicines, China Phar-
maceutical University, Nanjing 210009, China.
** Corresponding author. State Key Laboratory of Natural Medicines, China Phar-
maceutical University, Nanjing 210009, China.
E-mail addresses: youqidong@gmail.com (Q.-D. You), sunhaopeng@163.com
(H.-P. Sun).
http://dx.doi.org/10.1016/j.ejmech.2016.04.032
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.

2
D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
antagonists to inhibit H3K4 methyltransferase activity can be a
potential therapeutic strategy to treat leukemias carrying MLL1
fusion proteins.
Recently, a series of MLL1 Win motif containing peptides were
reported to bind to WDR5 and disturb the interaction of MLL1-
WDR5 interaction [17]. Then researchers found the minimum
MLL1 derived peptide Ac-Ala-Arg-Ala-NH2, with a high affinity
binding to WDR5 [18]. Peptidomimetic MM-102 and cyclized
peptidomimetic MM-401 (Fig. 1) were modified based upon Ac-
Ala-Arg-Ala-NH2 to target MLL1-WDR5 interaction with higher
affinity [19]. All of the peptidomimetics contain a conserved argi-
nine with poor cell-permeability. To date, only one category of
small molecular antagonists were reported to interfere the inter-
action of MLL1-WDR5, the best compound OICR-9429
(Kd ¼ 93 28 nM) was reported as a potent and selective WDR5
Fig. 2. The structure of four groups of inhibitors.
atmosphere at room temperature. Catalyzed with Dichlorobis(-
triphenylphosphine)palladium(II), Suzuki coupling reactions were
employed in 1, 4-dioxane to yield target compounds 18~25
(Scheme 1), bearing an aromatic ring in the 5-position. 25 was
reacted with reductive Tin (II) dichloride dehydrate in ethyl acetate
to get the target compound 26. Compounds 29~32 were synthe-
tized following the synthetic route of compounds 17~26 from 4-
bromo-2-fluoronitrobenzene 5b (Scheme 1).
Compound 27 was accomplished under the similar reaction
with the first analogue. But the 5-subsitution was achieved in the
first step to give a 5-phenyl product through Suzuki coupling re-
action catalyzed by Tetrakis (triphenylphosphine) platinum (0) in
THF. Also the intermediate 14 was reacted with chloride of acid 9
nitrified from acid 3 to give target compound 27 with a nitro
(Scheme 2).
WDR5-47 was synthetized from 2-fluoro-5-nitroniline accord-
ing to the published reference [21]. The reaction of compound 15
with N-methyl piperazine in DMF gave the corresponding amino
16. The amino was then treated with the chloride of acid 3 and 9 to
generate target WDR5-47 and 28. Then the nitro of WDR5-47 was
converted into amino with reductive in the following step to yield
compound 17 (Scheme 3). The synthesis of compounds 33~36 fol-
lowed the synthetic route of WDR5-47 with different Benzene-
sulfonyl chlorides (Scheme 4).
Different anilines reacted with chloride of 2-fluoro-5-
nitrobenzoic acid to product intermediates 37a~40a, then treated
with N-methyl piperazine in DMF gave the target compounds
37~40 (Scheme 5).
antagonist [20]. WDR5-47 (IC50 ¼ 0.3
mM), with a low molecular
weight, had moderate affinity of binding to WDR5 [21,22], thus
WDR5-47 was selected as a hit to optimize to achieve compounds
with higher affinity to MLL1-WDR5 interaction.
In the present study, we have designed and synthetized series of
small molecular inhibitors of MLL1-WDR5, based on the co-crystal
structure of WDR5-47 and WDR5 protein complex. With modifi-
cation of compound WDR5-47, a more potent inhibitor 23 was
identified. To our best knowledge, 23 was one of the most potent
small molecular, which disturbed the interaction of MLL1-WDR5
with IC50 value was 104 nM and about 3-times more potent than
compound WDR5-47 in fluorescence polarization (FP) assay. The
SAR of these series of compounds was discussed along with the
docking study, which may stimulate more potent inhibitors in
future.
2. Results and discussion
2.1. Chemistry
The structure of compounds shown in Fig. 2 can be divided into
four groups. In the first group, only R1 was substituted (17~26); but
in the second, both R1 and R2 were substituted (27~28); in the third
group, the substituents of the first group (R1) were moved to the 4-
position, with no substituent in R2 (29~32). In the fourth group, the
linker between two rings was changed (33~40).
FriedeleCrafts acylation reaction was performed to synthetize
1-(2-chloro-4-fluoro-3-methylphenyl) ethanone 2 from 2-chloro-
6-fluorotoluene and acetyl chloride. Then a haloform reaction was
employed in 1, 4-dioxane to provide the acid 3 [23]. The fluorine of
5-bromo-2-fluoronitrobenzene 5a was displaced by N-methyl
piperazine generating compound 6a. 6a was reacted with reductive
Tin (II) dichloride dehydrate in ethyl acetate to get the aniline 7a.
The key intermediate benzamide 8a was prepared with aniline 7a
and the chloride of acid 3 in anhydrous dichloromethane under N2
2.2. Binding assays
2.2.1. Binding affinity evaluation of compounds disturb the
interaction of MLL1-WDR5 by FP assay
10 Peptidomimetic of Win motif (ARTEVHLRKS) for WDR5 was
synthesized, C-terminal-labeled with 5-carboxy fluorescein (5-
FAM) tagged tracers linked through the side chain of a Lysine res-
idue next to the two 6-amino hexanoic acid linker with the Serine
Fig. 1. Examples of reported inhibitors of MLL1-WDR5 PPI.

D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
3
Scheme 1. Synthesis of compounds 18~26 and 29~32. Reagents and Conditions: a. CH3COCl, AlCl3, DCM, rt. 2 h; b. Br2, NaOH, 1,4-dioxane, 0 ꢀC, 2 h; c. SOCl2, reflux, 6 h; d. N-methyl
piperazine, DIPEA, DMF, 80 ꢀC, 4 h; e. SnCl2.2H2O, EA, reflux, 4 h; f. compound 4, pyridine, DCM, rt. 4 h; g. boronic acid, Pd(PPh3)Cl2, Cs2CO3, 1,4-dioxane, 100 ꢀC, N2, 20e36 h; h.
SnCl2.2H2O, EA, reflux, 8 h.
Scheme 2. Synthesis of compounds 27. Reagents and Conditions: a. H2SO4, HNO3, rt. 3 h; b. SOCl2, reflux, 6 h; c. boronic acid, Pd(PPh3)4, Na2CO3, THF, reflux, N2, 20 h; d. N-methyl
piperazine, DIPEA, DMF, 80 ꢀC, 2 h; e. SnCl2.2H2O, EA, reflux, 4 h; f. compound 10, pyridine, DCM, rt. 4 h; g. SnCl2.2H2O, EA, reflux, 4 h; h. 1 M/Li(OH), THF, rt. 8 h.
Scheme 3. Synthesis of compounds 17, WDR5-47, and 28. Reagents and Conditions: a. N-methyl piperazine, DIPEA, DMF, 80 ꢀC, 8 h; b. compound 4 or 10, pyridine, DCM, rt. 4 h; c.
SnCl2.2H2O, EA, reflux, 7 h.
[18]. Compound binding assays were performed in a 60
m
L volume
position (R1) was accepted (Table 1). But the compounds lost in
potency, when the substituents were moved from 5-position to 4-
position (compounds 29~32 versus 19, 23, 25, 26). Compounds
substituted at 4-position with an extended structure can't inserted
at a constant concentration of 3 nM 10mer-Thr-FAM probe and
8 nM WDR5 protein (See supplying information). The results
showed that the introduction of one aromatic ring into the 5-

4
D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
Table 1
Binding affinity to WDR5 of compounds 17 to 32 with R1, R2 and R3 modification
disturbing the interaction of MLL1 probe-WDR5.
Compd.
R1
R2
R3
IC50 (nM)
>20
Scheme 4. Synthesis of compounds 33~36. Reagents and Conditions: a. N-methyl
piperazine, DIPEA, DMF, 80 ꢀC, 8 h; b. benzenesulfonyl chlorides, pyridine, DCM, rt.
48 h.
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
eNH2
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eNO2
eNO2
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
eH
4-COOHePh
4-Pyridyl
4-NO2ePh
4-NH2ePh
eH
mM
3-COOHePh
4-COOHePh
4-CNePh
ePh
4-FePh
4-Pyridyl
5-Pyrimidyl
4-NO2ePh
4-NH2ePh
ePh
eNO2
eH
eH
eH
eH
eNO2
1604.0 178.5
660.9 61.8
198.5 17.2
465.7 24.6
392.6 82.1
103.9 11.9
733.3 15.6
127.4 13.2
206.1 26.4
207.2 34.7
130.0 14.2
into the active cavity of WDR5 protein, while compounds
substituted at 5-position may be suitable for the cavity occupied by
WDR5-47 (Fig. 3). The modification of 5-position proved to have a
variable impact on potency. All of compounds substituted at 5-
position, with the exception of 18 and 19, bearing an aromatic
ring resulted in an appreciable potency gain. The advantage for an
aromatic substituent at 5-position was made clear by the relative
activity of compound 25 versus WDR5-47 and compound 26 versus
17. The aromatic ring of 5-position may occupy the hydrophobic
groove of WDR5, surrounded by side chains of Phe133, Phe149 and
Tyr191 (Fig. 3). Also, being close to Phe149, Tyr191 and Phe133, the
>20
>20
>20
>20
m
m
m
m
M
M
M
M
WDR5-47
338.6 31.7
aromatic ring of 5-position can form pep stacking interaction with
the residues for their increased potency of this series of compounds
(Fig. 4).
assay (Fig. 5).
The position of substituents in aromatic ring had important ef-
fect on the potency to interfere the interaction of WDR5-MLL1.
Changing the carboxyl from 4-position (19) to 3-position (18) of the
aromatic ring resulting in 3-fold loss of potency. The amide of
compound 18 failed to make an indirect hydrogen with Cys261 like
19 and WDR5-47 (Fig. 4), which may resulted in the loss of potency
of compound 18. Maybe different position of substituents affected
the conformation of compounds binding to WDR5. 3-Carboxyl of 18
failed to make any hydrogens bond with Tyr191 and may affect the
conformation of amide resulting in poor potency (Fig. 4a). Sub-
stituents in 4-position perhaps have greater potency. Different
substitutes introduced into 4-position of the aromatic ring was
tolerated, except compound 19 bearing a carboxyl. This position
was located near to the solvent area of WDR5. Compared 20, 22, 23,
26 with 21, it was found that compounds with hydrophilic sub-
stituents may be more appropriate to bind with WDR5, which lead
to a little increase in potency. In addition, the affinity of 26 versus
25, 21 versus 23 showed that an electron withdrawing group at the
4-position of the aromatic ring was more suitable than electron-
donating group. 23 was the most potent compound bearing both
a hydrophilic aromatic ring and an electrondrawing group in FP
2.2.2. Binding affinity evaluation with isothermal titration
calorimetry (ITC)
ITC experiments (See supplying information) were carried to
confirm the binding of compounds to WDR5 for future optimiza-
tion. According to the curve-fitting analysis of compounds 23 and
28, a strong enthalpy component to binding and a weak entropy
were observed in both compounds 23 and 28, which illustrated
hydrophilic contacts might contribute to the binding. In contrast to
WDR5-47, compound 23 exhibited approximately 2:1 stoichiom-
etry as determined by ITC, which need to investigate in future. With
the dissociation constant Kd of 132.5 nM, compound 23 was
confirmed to bind to WDR5 and interfere the interaction of MLL1-
WDR5 (Fig. 6). So compound 23 with a pyridyl in 5-position will be
selected for optimization in future.
In previous study, Yuri Bolshan et al. gave ideas that 4-F sub-
stituent of the benzamide moiety may serve to increase potencies
by strengthening the amide to Ser91 hydrogen bond interaction via
an electron withdrawing effect [21]. To prove this idea, an electron
withdrawing group-nitro was introduced into the o-position of F of
the benzamide moiety to decrease the electron density. To our
Scheme 5. Synthesis of compounds 37~40. Reagents and Conditions: a. SOCl2, reflux, 6 h; b. anilines, pyridine, DCM, rt. 2 h; c. N-methyl piperazine, DIPEA, DMF, rt, 2 h.

D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
5
Fig. 3. The binding model of compounds 23 (green) and WDR5-47 (white) to WDR5 protein. Compounds 23 and WDR5-47 occupied the similar central cavity of WDR5 binding
pocket. Binding sites of compounds 23 (b) and WDR5-47 (a) to WDR5 were similar with a stacking interaction (orange) with Phe133, direct and indirect hydrogen bonds (blue)
pep
with Ser91 and Cys261, but compound 23 was involved in additional hydrophobic groove surrounded by Phe149, Phe133 and Tyr191, which greatly increased the affinity of
compound 23. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4. The superimposing model of WDR5 in complex with 18 and WDR5-47 (a), compound 19 and WDR5-47 (b). Both 18 and 19 adopt similar pose in the WDR5 binding pocket,
but the conformation of benzamide of these two compounds were twist. That may accounted for the decrease of potency. The amide of compound 18 failed to make an indirect
hydrogen with Cys261 like 19 and WDR5-47, which may resulted in the loss of potency of compound 18.
surprise, both compounds resulted in an appreciable potency gain
through nitrifying the o-position of F of compound WDR5-47 and
21, leading to more active compounds 28 and 27, respectively
(Table 1).
In order to understand the binding model of our compounds to
WDR5 deeply, the docking simulation was performed to analyze
compound 23 binding to WDR5. Compound 23 was docked into the
site of WDR5 (PDB ID: 4IA9) using CDOCKER module in Discovery

6
D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
Fig. 5. Competitive binding curves for WDR5-47, compounds 23 and compound 28 as evaluated using FP-based assay.
Fig. 6. Assessing the binding affinity of compounds 23 and 28 to WDR5 by ITC. Upper panels show heat of binding plotted versus time. Lower panels show fit to a single-site binding
model to the binding isotherms. Kd (S.D.) derived from the fit is indicated.
Studio 3.0.
As expected, similar to the structure of WDR5-47, 23 occupied
the central cavity of WDR5 that normally accommodates
future optimization.
Overall, introducing an aromatic ring into the 5-position was
tolerated, but the substituents at 4-position were not acceptable. A
a
conserved arginine of MLL1 Win motif (Fig. 3). The binding model
of 23-WDR5 recapitulates most interactions of WDR5-47 that the
hydrogen bonds between amide and the side chains of Cys261 and
Ser91 of WDR5, the indirect hydrogen bond between protonate N-
Table 2
Binding affinity to WDR5 of compounds 33 to 40 with the linker between two rings
and R4 modification disturbing the interaction of MLL1 probe-WDR5.
methylpiperazine and Cys261, the
pep stacking interaction with
Phe133, and the hydrophobic interaction with the pocket formed
by Ala65, Ala47, and Leu321 [21]. But the 5-pyridyl of compound 23
may occupy the hydrophobic groove of WDR5, surrounded by side
chains of Phe133, Phe149 and Tyr191 instead of the cleft flipped by
Phe133 and Phe263, increasing the interaction with WDR5. More-
over, in the docking model, the pyridyl ring was located in the
solvent area of WDR5 in a suitable conformation, which was
agreement with high affinity of hydrophilic substitutes to WDR5.
The amide of WDR5-47 played vital roles in driving the mo-
lecular binding to residues of Ser91 and Cys261 of WDR5 protein
[21]. To explore the linker between the two rings, we replaced the
NHCOe with eCONHe and eSO2NH- (compounds 33~40). Unfor-
tunately, almost all compounds lost potency in blocking the inter-
action of MLL1-WDR5 (Table 2). This may because the amide
formed critical hydrogen bonds, which were strictly in distance and
orientation (Fig. 7). Modification of amide lead to completely loss of
the activity showing the necessity of the hydrogen bond between
amide with Ser91 and Cys261. So the amide should be retained in
Compd.
X
R4
IC50 (mM)
32
34
35
36
37
38
39
40
eNHSO2e
eNHSO2e
eNHSO2e
eNHSO2e
eCONHe
eCONHe
eCONHe
eCONHe
eNHCOe
4-fluoro
4-methoxyl
3,4-dimethoxyl
2,4,6-trimethyl
4-fluoro-2-chloro-3-methyl
3-methoxyl
2,4-difluoro
2-chloro
4-fluoro-2-chloro-3-methyl
>20
>20
>20
>20
11.4 2.1
>20
>20
>20
WDR5-47
338.6 31.7 (nM)

D.-D. Li et al. / European Journal of Medicinal Chemistry 118 (2016) 1e8
7
Fig. 7. The binding model of compounds 37 (a) and WDR5-47 (b). Changing the linker between the two rings, 37 lost the interaction with Cys261 like the amide of WDR5-47. The
linker between the two rings affected hydrogen bonds with WDR5, which were strictly in distance and orientation.
WDR5-47 and WDR5 protein (PDB ID: 4IA9, Fig. 3), we can see that
4-F of compound WDR5-47 only make weak hydrogen bond
interaction indirectly via a water molecule with side chain of
Asp107. So a polar group need to introduce at the o-position of 4-F
of the benzamide to explore the hydrogen bond interaction with
Asp107 in future study.
Conflicts of interest
The authors declare no other conflicts of interest.
Acknowledgments
This work was supported by the project 81230078 (key pro-
gram), 81202463 (youth foundation) and 91129732 of National
Fig. 8. The SAR of this series of compounds. The amide was necessary for binding to
Natural Science Foundation of China, Program of State Key Labo-
WDR5 (orange). An aromatic ring in the 5-position (blue) was tolerated, but sub-
ratory of Natural Medicines, China Pharmaceutical University (No.
stituents at 4-position were not acceptable (black). The hydrophilic or electron with-
JKGQ201103), 2012AA020301 of 863 program, 2010ZX09401-401,
2009ZX09501-003 and 2014ZX09507002-005-015 of the National
Major Science and Technology Project of China (Innovation and
Development of New Drugs), Specialized Research Fund for the
Doctoral Program of Higher Education (SRFDP, 20130096110002).
The authors declare no other conflicts of interest.
drawing substituents in the aromatic ring were suitable at 5-position (green). An
electron withdrawing group was introduced at the o-position of 4-F of the benzamide
increasing in potency (red). (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)
hydrophilic or electron withdrawing substituents in the aromatic
ring were suitable. The amide was necessary for binding to WDR5.
And an electron withdrawing group nitro was introduced at the o-
position of 4-F of the benzamide greatly increasing in potency
(Fig. 8). With the modification of compound WDR5-47, a more
potent compound (23) was designed, which binds to WDR5 with
IC50 ¼ 104 nM in FP assay.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2016.04.032.
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