Design and synthesis of benzylpiperidine inhibitors targeting the menin–MLL1 interface

Article abstract of DOI:10.1016/j.bmcl.2016.07.074

Menin is an essential oncogenic cofactor for mixed lineage leukemia (MLL)-mediated leukemogenesis, functioning through its direct interaction with MLL1 protein. Therefore, targeting the menin–MLL1 protein–protein interface represents a promising strategy

Full text of DOI:10.1016/j.bmcl.2016.07.074

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of benzylpiperidine inhibitors targeting
the menin–MLL1 interface
Jing Ren a,c,y, Wei Xu b,c,y, Le Tang a, Minbo Su b, Danqi Chen a, Yue-Lei Chen a,c, Yi Zang b, Jia Li b,c
,
Jingkang Shen a,c, Yubo Zhou b,c, , Bing Xiong a,c,
⇑
⇑
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China
b The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, PR China
c University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Menin is an essential oncogenic cofactor for mixed lineage leukemia (MLL)-mediated leukemogenesis,
functioning through its direct interaction with MLL1 protein. Therefore, targeting the menin–MLL1 pro-
tein–protein interface represents a promising strategy to block MLL-mediated leukemogenesis. On the
basis of co-crystal structure analysis, starting from thienopyrimidine chemotype, we have investigated
the detailed structure–activity relationship of the piperazinyl-dihydrothiazole moiety. Several com-
pounds were found with potent inhibitory activity against menin and better activities in cell-based
experiments than MI-2-2. Molecular docking analysis revealed a less explored subpocket, which could
be used for the design of new menin–MLL1 inhibitors.
Received 16 April 2016
Revised 7 July 2016
Accepted 29 July 2016
Available online xxxx
Keywords:
Menin
Mixed lineage leukemia
MLL1
Ó 2016 Elsevier Ltd. All rights reserved.
SAR
Inhibitor
Mixed lineage leukemia (MLL) is a very aggressive blood cancer
that predominantly occurs in pediatric patients. Chromosomal
translocations involving the MLL gene at 11q23 are observed in
more than 70% of infant acute lymphoblastic leukemia (ALL) and
5–10% of acute myeloid leukemia (AML) in adults.1,2 Studies
showed that fusion of MLL gene with one out of over 60 partner
genes results in expression of chimeric MLL fusion proteins, which
enhance proliferation of hematopoietic cells, block hematopoietic
differentiation, and ultimately lead to acute leukemia.3,4 In addi-
tion, patients with mixed lineage leukemia have very poor progno-
sis and respond poorly to currently available treatments,5,6
emphasizing the urgent need for developing novel therapies.
The leukaemogenic activity of mutant MLL proteins depends on
their interactions with menin, a product of the multiple endocrine
neoplasia type 1 (MEN1) tumor suppressor gene.7 As a regulator of
target gene expression, menin is a highly specific binding partner
of MLL1 and MLL1 fusion proteins.8–10 MLL1 interacts with menin
through two N-terminal motifs: The high-affinity binding part
called menin-binding motif 1 (MBM1) and the low-affinity part
called menin-binding motif 2 (MBM2).11 Since the N terminal of
most MLL1 fusion proteins remain unchanged, disruption of the
protein–protein interaction between menin and MLL1 fusions
could treat many types of mixed lineage leukemia. Therefore,
menin was regarded as a critical oncogenic cofactor of MLL1 fusion
proteins in acute leukemia, and intercepting the protein–protein
interaction between menin and MLL1 consequently became a very
attractive therapeutic strategy for new drug design for the MLL
leukemia patients.12
Grembecka’s group pioneered the development of menin–MLL1
inhibitors and identified the thienopyrimidine MI-2-2 (1) as the
first small molecule targeting this protein–protein interaction
reported to date.13,14 Very recently, they further reported the opti-
mized inhibitor MI-503 (2) with high potency in cellular studies
and good in vivo efficacy in mice models of castration-resistant
tumors and MLL leukemia.15,16 On the basis of amino methyl piper-
idine chemotype, Grembecka et al. also discovered MIV-6 (3),
which binds to the same binding site of menin to block the
menin–MLL1 protein–protein interaction.17 In addition, the MLL1
derived peptidomimetic (MCP-1) (4) were recently reported as a
potent inhibitor to block the menin–MLL1 interaction. However,
the cellular activity of this peptidomimetic compound was not dis-
closed (Fig. 1).18
On the basis of the crystal structure analysis of menin MI-2-2
(1) complex, we first identified the close interaction of thienopy-
rimidine ring and the protein exemplified by a favorable CAF—
C@O dipolar interaction between the fluorine atom in MI-2-2 and
⇑
Corresponding authors. Tel.: +86 021 50801313 (Y.Z.), +86 021 50806600x5412
(B.X.).
E-mail addresses: ybzhou@simm.ac.cn (Y. Zhou), bxiong@simm.ac.cn (B. Xiong).
These authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.bmcl.2016.07.074
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
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2
J. Ren et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
N
N
N
HN
S
N
N
N
MI-503 (2)
MI-2-2 (1)
N
NH
N
CF3
N
CF3
N
S
N
S
CN
HN
H
N
NH2
NH
N
O
O
O
O
N
HN
HN
O
O
H
N
MIV-6 (3)
H2N
N
MCP-1 (4)
NH2
O
F
F
Figure 1. Small-molecular and peptidomimetic inhibitors to block the menin–MLL1 interaction.
the backbone of His181. Next, we noticed that the piperazinyl-
dihydrothiazole part formed van der Waals interactions with the
flat surface centered at residue Tyr323 of menin. This subpocket
has large room to accommodate various chemical groups and can
be explored for new chemical skeleton. Thus, we initialized a pro-
gram to investigate the detailed structure–activity relationship on
the piperazinyl-dihydrothiazole part (R group in Fig. 2). It was dur-
ing this work, that compound (2) was reported by Grembecka’s
group with a similar design rationale. Herein, we would like to
report on our detailed SAR study on the piperazinyl-dihydrothia-
zole moiety, and complement the results of Grembecka et al.
We have designed and assessed several structures with docking
study for variations of the R group. Based on the binding interac-
tion analysis, compounds 5–8 were selected for chemical synthesis
and tested with fluorescence polarization (FP) assay (see the Sup-
porting information for the experimental details).
CF3
CF3
S
N
S
N
S
N
N
R
N
N
N
MI-2-2
I C50 = 0.17 0.05 μ M
CADD
CF3
CF3
S
S
N
CN
O
N
N
N
NH
Compound 5 was designed by merging MI-2-2 (1) with com-
pound 3. Molecular docking showed the thienopyrimidine moiety
of 5 adopted a similar binding mode as MI-2-2 (1), and the ben-
zonitrile part reached the subpocket of residue Trp341 to form a
hydrogen bond. Compound 5 showed potent inhibitory activity
N
N
5
IC50 = 0.43 0.04 μ M
6
IR = 2% @ 20 μ M
CF3
CF3
(IC50 = 0.43 lM) in the FP assay, encouraging us to continue the
N
optimization. Although compounds 6–8 have similar structures
at the R part, their inhibitory activities against menin showed sig-
nificant difference. Compounds 7 and 8 were potent inhibitors,
while compound 6 did not show activity at 20 lM. To elaborate
the SAR of this part, three potent compounds (5, 7 and 8) were fur-
S
N
S
NH
N
NH
N
N
N
7
I C50 = 2.24 0.09 μ M
8
I C50 = 0.47 0.18 μ M
ther optimized.
Figure 2. The modification of piperazinyl-dihydrothiazole part (R group).
Based on compound 5, compounds 9–11 were designed for the
investigation of the relationship of the linker and binding activity.
We varied the atom type and length of the linker between piper-
azine and benzonitrile, and found that the most potent inhibitor
was compound 5 (n = 3, X = O). Replacing the atom x with N
decreased the activity about 3 folds (compound 9, IC50 = 1.54 lM),
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J. Ren et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 1
possibly due to the orientation change of benzonitrile moiety.
Menin inhibitory activity of compounds 9–11
Reducing the n length from 3 to 2 resulted in compounds 10 and
11 (x = O, N respectively) with decreased inhibitory activity about
20 folds, emphasizing the necessity of proper length to maintain
the hydrogen bond interaction with residue Trp341 (Table 1).
From compound 7, we first performed the optimization of the
R1 substituent on the phenyl ring. Introducing electron-donating
methyl or methoxy group resulted in compounds (12 and 13) with
similar activity. In contrast, introducing electron-withdrawing
cyano or trifluoromethyl group resulted in compounds (14 and
15) with more than 20-fold decrease in the inhibitory activity.
Additionally, compound 16 with fluorophenyl ring showed similar
activity as compound 7 (Table 2).
CF3
S
N
n
X
N
N
CN
N
Compd
N
x
Menin
IC50 (lM)
9
10
11
3
2
2
N
O
N
1.54 0.20
>20
>20
Eventually, we focused on the optimization of compound 8.
Molecular docking indicated that the thienopyrimidine part of
compound 8 adopted a similar mode with MI-2-2, and the benzyl
part attached to piperidine ring interacts with the Pro13 subpocket
of menin. We explored the SAR of the benzyl moiety, and found
that the absence of benzyl group significantly decreased the inhibi-
Table 2
Menin inhibitory activity of compounds 12–16
4
R1
3
CF3
tory activity for about 70-fold (compound 17, IC50 = 32.81 lM).
S
N
Similarly, replacing phenyl ring with more steric–hindered group
(18–20) showed much weaker activity. We replaced the benzyl
group with phenyl ethyl group to increase the flexibility, and the
resulting compound (21) showed slightly decreased activity about
4-fold. Aliphatic moieties were also introduced, yielding com-
pounds 22–23 with slightly weaker activity than compound 8. By
using the bioisosterism rules, we replaced the phenyl ring with
alkynyl group and heterocyclic rings to produce compounds 24–
NH
N
N
Compd
R
Menin
IC50
Compd
R
Menin
IC50 (lM)
(l
M)
12
13
14
3-Me
4-OMe
4-CN
3.80 0.41
1.07 0.12
33.4%@20 lM
15
16
4-CF3
4-F
18.5%@20
1.17 0.00
lM
27, and among which, compound 26 (IC50 = 0.22 lM) contained a
thiophene ring was about 2-fold more potent than compound 8
(Table 3).
We then explored the substitutions on the phenyl ring of com-
pound 8. With methoxyl substitution, the inhibitory activity of
compound 28 was similar to compound 8. In contrast, introduction
of 4-trifluoromethyl or 4-cyano resulted in compounds 29 and 30
with decreased inhibitory activity by more than 20-fold. But the
introduction of fluorine atom (compound 31) did not show much
decrease of activity. Similarly, 3-amino substituent reduced the
activity slightly, and 3-nitro lowered the activity significantly.
Overall, compounds substituted with electron-donating groups
were more potent than that with electron-withdrawing groups
(Table 4).
The molecular docking structure of menin with compound 8
revealed several negatively charged residues around the phenyl
ring, such as Asp285 and Glu363. On the basis of structure data,
we anticipated that introducing an appropriate positively charged
group, such as an amino moiety, should result in additional favor-
able electrostatic interactions with adjacent acidic residues. Differ-
ent linear amino alkyl groups were introduced to the 3-position of
phenyl ring and most of these compounds exhibited preferable
activity except for compound 37, which may be due to its steric
hindrance from N,N-dimethyl group. We also introduced piperi-
dine to the phenyl ring. The resulting compound 40 was found
with moderate inhibitory activity and compound 39 with weaker
activity (Table 5 and Fig. 3).
Table 3
Menin inhibitory activity of compounds 17–27
CF3
R
N
S
NH
N
N
Compd
R
Menin
Compd
R
Menin
IC50 (lM)
IC50
(
l
M)
17
18
H
32.81 6.77 23
5.67 0.56
2.4%@20
lM
24
25
26
31.3%@20
4.69 0.11
0.22 0.12
lM
O
19
20
15.6%@20
lM
S
N
4.6%@20
lM
21
22
1.80 1.39
0.77 0.03
27
2.70 0.42
We selected compounds 34 and 40 to dock into menin utilizing
the software GLIDE. The amino groups of compound 34 in the side
chain formed electrostatic interactions with Asp285, with a dis-
tance of 2.63 Å between N and O. The amino group of compound
40 extended to the opposite direction of Asp285, forming electro-
static interactions with Glu363. These predicted binding mode
highlighted that the positively charged groups in ligands can con-
tribute new interactions, which may provide a new direction for
the design of new inhibitors targeting the menin-MLL1 interaction.
Based on the previous studies, human leukemia cells expressing
MLL-AF4 were sensitive to menin inhibitors, such as MV-4-11 cell
line.19 However, K562 cell, another kind of chronic myelogenous
leukemia (CML) cell, is independent of the MLL1-menin proteins
and should not be sensitive to menin inhibitors. Disruption of the
menin–MLL1 fusion protein interaction is expected to result in
growth arrest of MLL leukemia cells. Therefore, we selected several
compounds to test their activity in MV-4-11 cells and K562 cells
(see the Supporting information for the experimental details). As
expected, strong and dose-dependent inhibition of cell prolifera-
tion was observed for compounds 5, 8, 26 and 35 in MV-4-11 cells,
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J. Ren et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 4
Table 6
Menin inhibitory activity of compounds 28–33
The in vitro anti-proliferation activities of 14 compounds in MV-4-11 and K562 cells
Compd
MV-4-11
IC50 M)
K562
IC50
Compd
MV-4-11
IC50 M)
K562
IC50 (lM)
3
R1
4
(
l
(
l
M)
(
l
CF3
5
9
1.02 0.37
2.69 0.12
6.49 1.47
0.79 0.46
1.02 0.04
2.42 0.28
6.32 1.25
9.12 5.63
>20
>20
>20
>20
7
13
16
34
35
36
38
MI-2-2
2.33 0.30
1.28 0.09
2.98 0.20
4.15 0.95
0.39 0.07
3.49 1.15
1.65 0.26
0.64 0.11
>20
>20
>20
>20
>20
>20
N
S
22
26
8
28
31
NH
N
N
>20
>20
Compd
R
Menin
IC50
Compd
R
Menin
IC50 (lM)
9.51 7.83
>20
(
l
M)
28
29
30
4-OMe
4-CF3
4-CN
0.64 0.10
31
32
33
4-F
3-NH2
3-NO2
2.00 1.02
1.26 0.21
43%@20 lM
Notes: Cell proliferation assay was done according to the method mentioned in the
Materials and methods section, where cell were treated with drugs for 7 days. The
IC50 values represent the mean SD of triplicate determinations.
ꢀ2.5%@20
l
M
25%@20
lM
HOXA9
Table 5
Menin inhibitory activity of compounds 34–40
1.2
1
CF3
0.8
0.6
0.4
0.2
0
N
R
S
NH
N
N
Compd
R
Menin
IC50
Compd
R
Menin
IC50 (lM)
(
l
M)
O
O
H
N
NH2
NH2
34
35
1.22 0.14 38
0.67 0.17 39
O
O
1.12 0.08
13.39 11.12
Figure 4. Quantitative real-time PCR analysis of HOXA9 expression in MV-4-11
cells following 6 day incubation with compounds 26, 35 and MI-2-2. Expression of
HOXA9 has been normalized to â-actin and is referenced to the DMSO-treated cells.
Data represent the mean values for triplicates SD. The experiment was performed
3 times.
NH
O
O
O
N
36
37
0.78 0.12 40
2.35 1.18
N
7.35 5.36
N
expression of HOXA 9 in two cell lines transformed by transduction
of MLL-AF9 fusion genes.21 To assess whether our compounds
affect the expression level of HOXA9, we performed quantitative
real-time PCR (qRT-PCR) experiments in human MLL leukemia cell
MV-4-11 (see the Supporting information for the experimental
details). Indeed, treatment with compound 26 or 35 resulted in a
strong and dose dependent reduction in the expression level of
Hoxa9 as compared to the DMSO control, with about 70% decrease
in Hoxa9 level upon treatment with 10 lM of 26. The effect of
compound 26 on expression level of target genes is slightly more
potent than the control MI-2-2 (Fig. 4).
In summary, based on the analysis of currently available inhibi-
tors, including skeleton structure, drug-likeness and binding mode,
we selected MI-2-2 (1) and made SAR study on the piperazinyl-
dihydrothiazole moiety. The piperazine-dihydrothiazole group
with IC50 6 1 lM, which is consistent with its higher binding activ-
ity against menin. From the Table 6, these compounds have a very
limited effect on the proliferation of K562 cells, demonstrating pre-
ferred selectivity toward MLL1 fusion transformed cells.
HOXA9 is a part of the homeobox gene family, involved in set-
ting the body plans of animals.15 It is likely that HOXA9 would dis-
play increased expression in cells with higher differentiation
potentials.17 HOXA9 knockout mice have been shown to develop
a reduction in the number of circulating common myeloid progen-
itor cells, which differentiate into erythroid progenitor cells.20 The
menin–MLL1 fusion protein interaction is required for the mainte-
nance of high expression level of HOXA9 in MLL leukemia cells and
for leukemic transformation by MLL fusions. And as described by
Jizhou et al., the excision of menin can reduce about 70–80%
Figure 3. Docking study on compounds 34 (A) and 40 (B) in menin binding site. The menin protein is shown in cartoon style, while the ligands 34 and 40 are shown in stick
model. The residues forming important charged interactions are illustrated in stick model.
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J. Ren et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
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binding activity (IC50 = 0.47 M). Medicinal chemistry optimiza-
l
tion of the hit 8 led to the discovery of a series of compounds with
potent inhibitory activity against menin and several of them
showed good activities in in vitro anti-proliferation assay and
cell-based functional studies on the HOXA9 gene regulation.
Molecular docking analysis of compounds 34 and 40 revealed that
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form salt bridged interactions with surrounding negatively
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identified menin–MLL1 inhibitors, it may provide the researchers
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We thank Dr. Yanhui Xu (Fudan University) and Dr. Min Lei for
the gift of recombinant full-length human Menin protein and FAM-
MLL1 peptide. We are grateful for financial support from the
National Natural Science Foundation of China (Grant No.
81273368, 81330076 and 81473094); The National Science &
Technology Major Project ‘Key New Drug Creation and Manufac-
turing Program’ of China (Grant No. 2014ZX09507-002 and
2013ZX09507001).
Supplementary data
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Supplementary data (schemes and procedures of chemical syn-
theses, conditions and protocols of the biological assays) associated
with this article can be found, in the online version, at http://
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Please cite this article in press as: Ren, J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.07.074