Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists

Article abstract of DOI:10.1016/j.bmcl.2020.127676

We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC₅₀ = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC₅₀ = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.

Full text of DOI:10.1016/j.bmcl.2020.127676

Journal Pre-proofs
Design, synthesis and biological evaluation of new bivalent quinazoline ana‐
logues as IAP antagonists
InHwan Bae, Daejin Kim, JaeYul Choi, JiSook Kim, MinJeong Kim,
BoKyung Park, YoungHoon Kim, YoungGil Ahn, Ha Hyung Kim, Dae
Kyong Kim
PII:
S0960-894X(20)30787-3
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127676
BMCL 127676
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Bioorganic & Medicinal Chemistry Letters
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Revised Date:
Accepted Date:
21 September 2020
30 October 2020
1 November 2020
Please cite this article as: Bae, I., Kim, D., Choi, J., Kim, J., Kim, M., Park, B., Kim, Y., Ahn, Y., Hyung Kim,
H., Kyong Kim, D., Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP
antagonists, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127676
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Short communication
Title
Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP
antagonists
InHwan Baea,c,#, Daejin Kima,c,#, JaeYul Choic, JiSook Kimc, MinJeong Kimc, BoKyung Parka,
YoungHoon Kimc, YoungGil Ahnc, Ha Hyung Kimb,*, and Dae Kyong Kima,*
aDepartment of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang
University, 84, Heukseok-gu, Seoul, 06974, Republic of Korea
bBiotherapeutics and Glycomics Laboratory, College of Pharmacy, Chung-Ang University, 84,
Heukseok-gu, Seoul, 06974, Republic of Korea
cHanmi Research Center, Hanmi Pharm. Co. Ltd., 550 Dongtangiheung-Ro, Hwaseong-Si,
Gyeonggi-Do, 18469, Republic of Korea
E-mail addresses:
InHwan Bae : ihbae@hanmi.co.kr, Daejin Kim : daejini93@hanmi.co.kr, JaeYul Choi :
alchemistj@hanmi.co.kr, JiSook Kim
:
sook80@hanmi.co.kr, MinJeong Kim
:
minjeong.kim@hanmi.co.kr, BoKyung Park : parkbkp@naver.com, YoungHoon Kim :
yhkeem@hanmi.co.kr, YoungGil Ahn : ygahn@hanmi.co.kr, Ha Hyung Kim :
hahyung@cau.ac.kr, Dae Kyong Kim : kimdk@cau.ac.kr
* Corresponding authors
Ha Hyung Kim Ph.D., Biotherapeutics and Glycomics Laboratory, College of Pharmacy,
Chung-Ang University, 84, Heukseok-gu, Seoul, 06974, Korea. E-mail: hahyung@cau.ac.kr
Dae Kyong Kim Ph.D., Department of Environmental & Health Chemistry, College of
Pharmacy, Chung-Ang University, 84, Heukseok-gu, Seoul, 06974, Korea. E-mail:
kimdk@cau.ac.kr
# These authors contributed equally to this work.
1

Abstract
We recently reported the biological evaluations of monovalent IAP antagonist 7 with good
potency (MDA-MB-231, IC50=19 nM). In an effort to increase cellular activity and improve
favorable drug-like properties, we newly designed and synthesized bivalent analogues based
on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the
identification of 27, which showed dramatic increase of over 100-fold (IC50=0.14 nM) and
caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly
support 27 as a promising bivalent antagonist for the development of an effective anti-tumor
approaches.
Keywords
IAP antagonist; BIR3; Apoptosis; SMAC mimetics; Bivalent
2

Apoptosis or programmed cell death serves a vital role in homeostasis of multicellular
organisms. Organisms are maintained by apoptotic process that regulate cell growth and death,
but, if it is inhibited by some other factors, it may result in pathological diversity like cancer,
autoimmune diseases, neuro-degenerative disorders, and others.1 In the tumor development
stages, such regulatory steps of apoptosis mediate IAPs (inhibitor of apoptosis proteins) to
accumulate within cells via overexpression, which inhibit programmed cell death of mutant
cancer cells undergoing the apoptotic stage.2,3 The various apoptosis signals (e.g., stimuli such
as DNA damage, chemical agents, and ultraviolet) can lead to the inhibition of the natural
apoptotic mechanism in the processes of development, growth, and metastasis of cancer cells.4
For these reasons, tumor cells resistance to apoptosis has been considered an important
mechanism in tumor progression, and accordingly, it has been suggested that exploiting the
difference between the mechanisms in tumor cells and those in normal cells may be an effective
anticancer therapeutic target.5,6
Natural IAP antagonists, SMAC (second mitochondria-derived activator of caspases)
have the key sequence of Ala(P1)-Val(P2)-Pro(P3)-Ile(P4). Which bind in a shallow surface
groove of selected BIR domains of these IAP proteins in an extended conformation. Many
research groups have published and disclosed monovalent IAP antagonists such as, LCL161,
1 (XIAP-BIR3 = 52.7 nM)7 and AT406, 2 (XIAP-BIR3 = 66.4 nM)8. Additionally, several
groups found out bivalents were shown to have more potent cellular activities than
monovalents.9 Because most monovalent compounds show selectivity for BIR3 over BIR2,
while some do not exhibit BIR2 binding affinity or have not been tested for this activity. In
contrast, bivalents containing two AVPI mimics with a linker by targeting both the BIR2 and
the BIR3 domains of XIAP showed further increased binding affinity and cellular activity.10
The first class of bivalents is AEG40730, 3, which was shown to have potential cellular activity
(XIAP-BIR3 = 100 nM, MDA-MB-231 = 0.23 nM).11 4 is based on AT-406 series containing
two monovalent IAP binding motifs enchain together via a flexible linker (XIAP-BIR3 = 134
nM, MDA-MB-231 = 5.7 nM) 12 (Fig. 1).
3

CF3
HN
O
N
O
O
HN
O
O
O
O
F
N
N
O
N
O
N
O
NH
NH
O
S
HN
N
O
NH
CF3
3
(AEG40730)
Aegera
1
(LCL161)
Novartis
O
H
N
O
O
N
N
N
O
N
N
N
N
H
N
O
O
NH
(CH2)10
N
H
H
N
O
O
H
O
H
HN
NH
N
N
N
N
HN
2
4
(AT-406)
Ascenta
University of Michigan
Figure 1. Chemical structures of previously reported bivalent IAP antagonists
We recently reported the biological evaluations of monovalent IAP antagonist 7
(HM90822) with submicromolar activities to cancer cell lines.13-15 7 is a potent dual IAP and
EGFR inhibitor with 80 nM of BIR3 binding affinity and 5.4 nM kinase activity of EGFR
wildtype. 7 is designed with the structure of an EGFR inhibitor that is distinct from other
monovalent antagonists and easily introduced into the Ile (P4) such as Amgen IAP antagonist
6.16 (Fig. 2) However, the monovalent antagonist 7 showed lower cellular activity than the
bivalent IAP antagonist, and also had strong inhibitory activity against CYP3A4. (data not
shown) In an effort to increase cellular activity and improve favorable drug-like properties, we
newly designed and synthesized bivalent antagonists containing various linker molecules based
on the quinazoline structure of 7.
P2
P3
P1
P4
N
N
N
O
H
O
O
NH
O
N
F
NH
HN
N
H
NH
O
NH
O
O
O
H2N
O
O
HN
HN
O
Cl
F
N
OH
N
5
6
7
Ala-Val-Pro-Ile (AVPI)
Amgen
Hanmi
HM90822
Figure 2. General design method of 7
4

In this paper, we demonstrated the design, synthesis and evaluation of a novel
quinazoline-based SMAC mimetics. The novel bivalent structures were synthesized consisting
of three moieties: tripeptide, quinazoline core and a commercially available diamine linker.
The main advantage of this core structure is that the substituents of various diamine linkers are
synthetically possible at the 4-position of the core. (Scheme 3, 4).
The key intermediate, quinazoline was synthesized as shown in Scheme 1. 4-chloro-
7-methoxy-6-nitroquinazoline, 12 was prepared from commercially available 2-amino-4-
fluorobenzoic acid, 8 via the four-step routes.17 Cyclization of 8 with formamide and N,N-
dimethylformamide gave the quinazolinone 9. Nitration of 6-position of 9 with fuming HNO3
gave the 10, and the product was treated with NaOMe and MeOH to provide the desired
compound 11. Finally, quinazoline core 12 was prepared by chlorination of 4-position (see
supplementary data).
O
O
O
O2N
F
OH
NH2
NH
NH
a
b
F
F
N
N
8
9
10
O
Cl
O2N
O
O2N
O
c
d
NH
N
N
N
11
12
Scheme 1. Reagents and conditions: (a) Formamide, N,N-Dimethylformamide, 180 ℃, 18 h,
82%; (b) H2SO4, HNO3, 110 ℃, 4 h, 79%; (c) NaOMe, MeOH, 65 ℃, 2 h, 98%; (d) POCl3,
SOCl2, 100 ℃, 3 h, 85%.
The other key intermediate, tripeptide 16 was synthesized as shown in Scheme 2.
Tripeptides were synthesized using commercially available (L)-form natural and unnatural
amino acids using amide coupling reagents. The carboxylic group of Boc-Pro-OH, 13 was
protected by BnOH and following Boc-deprotection with 4M HCl in Dioxane gave 14. Amide
coupling of 14 with Boc-Tle-OH by HATU/DIPEA and following Boc-deprotection gave the
15. The tripeptide 16 was obtained using standard peptide coupling condition and following
debenzylation. The other tripeptide, Boc-MeAla-Chg-Pro-OH was synthesized in the same
5

manner using Boc-Chg-OH instead of Boc-Tle-OH.
O
a, b
c, d
e, f
OH
N
O
O
N
N
OH
N
O
H
O
Boc
O
O
Boc
O
O
NH
H2N
N
13
14
15
16
Scheme 2. Reagents and conditions: (a) BnOH, EDCI, DIPEA, DMAP, DCM, rt, 22 h, >100%; (b) 4M
HCl in Dioxane, rt, 1 h, >100%; (c) Boc-Tle-OH, HATU, DIPEA, DCM, rt, 1.5 h, 89%; (d) 4M HCl in
Dioxane, rt, 1 h, >100%; (e) Boc-MeAla-OH, EDCI, DIPEA, DCM, rt, 16 h, 67%; (f) H2, Pd/C, MeOH,
rt, 2 h, 51%.
The bivalent synthesis of 24-33 were started from 12 which was prepared by a general
synthetic route via Scheme 3. as described below. The diamine-linker couplings of quinazoline
12 resulted in 17, followed by reduction of the nitro group with Fe under acidic condition to
give 18. The amine 18 was coupled with appropriate tripeptide, Boc-MeAla-Tle-Pro-OH or
Boc-MeAla-Chg-Pro-OH using EDCI as the amide coupling reaction. Finally, deprotection of
the Boc group resulted in the desirable structure of 19.
N
O
N
O
N
N
NO2
NH2
a
b
12
R2
R2
O2N
O
H2N
O
N
N
N
N
17
18
R2
H
N
H
N
N
N
N
N
c, d
R1
R1
O
O
O
N
N
O
O
O
O
O
NH
HN
N
H
N
H
19
Scheme 3. Reagents and conditions: (a) TEA, iPrOH, Diamine, 80 ℃, 4 h; (b) Fe, HCl, 50%
EtOH/DW, reflux, 8 h; (c) EDCI, Pyridine, Tripeptide, 60 ℃, 4 h; (d) 4M HCl in Dioxane, rt,
4 h.
We initially focused on 1,4-phenylenedimethanamine linked bivalent 23, which was
6

more potent than the benzylamine monovalent in 8-fold more potent in MDA-MB-231 cell
growth inhibition. Although the cellular inhibitory activity was increased compared to
monovalent HM90822, 7 the activity was still higher than competing bivalents. Instead of the
aromatic linker between two monomers, we wanted to choose a linker that would have
flexibility to improve binding interactions. To introduce a flexible linker, 24 linked with trans-
1,4-cyclohexane-bis(methylamine) was synthesized and showed the possibility of
derivatization by over 60-fold improved activity of 0.31 nM. However, 25 still had a strong
inhibitory activity of IC50=0.46 μM against CYP3A4.
Subsequent effort to overcome the above drawbacks, we focused on chain-length
optimization and stereochemistry using a relevant diamine-linkers. 25 with cis-1,4-
cyclohexane-bis(methylamine) instead of trans-1,4-cyclohexane-bis(methylamine) was
evaluated, but it had similar activity (MDA-MB-231, IC50=0.41 nM; CYP3A4, IC50<0.62 μM).
26 comprising cyclohexyl residue in (P2)-position showed an almost 3-fold decreased cellular
activity compared to 24 containing the tert-butyl analogues. Therefore, the remaining
derivatives were retained for (P2)-position with Tle. By reducing the chain length, 26-28 were
evaluated. 26 with a trans-1,4-Diaminocyclohexane linker had the best cellular activity
(IC50=0.14 nM) and moderate activity against CYP3A4 (IC50=3.56 μM), while 27 with a cis-
1,4-Diaminocyclohexane linker had the moderate activity against CYP3A4 (IC50=5.53 μM),
which had low cellular activity (IC50=5.93 nM). To gain a more detailed understanding of the
interactions of the non-cyclic linker-containing antagonists, we evaluated 30-32 containing
hydrocarbon-linker, ethylene glycol-linker and acetylene-linker, respectively. However, only
32 showed slightly increased CYP3A4 activity, and the structure-activity relationship through
its derivative synthesis was explored. The activity to MDA-MB-231 and CYP3A4 inhibition
of these compounds are presented in Table 1.
Table 1. Diamine linked-derivatives 23-32 synthesized via Scheme 3
R2
H
N
H
N
N
N
N
N
R1
R1
O
O
O
N
N
O
O
O
O
O
NH
HN
N
N
H
H
MDA-MB-231
CYP 3A4
(IC50, μM)
Compound
R1
R2
(IC50, nM)
7

N
H
H
N
23
24
25
26
27
28
29
30
31
32
t-butyl
t-butyl
t-butyl
cyclohexyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
t-butyl
4.30
0.31
0.41
1.03
0.14
5.93
2.30
0.30
-
N
H
H
N
0.46
<0.62
0.66
3.56
5.53
-
N
H
H
N
N
H
H
N
H
N
N
H
H
N
N
H
N
N
H
N
0.43
N
H
H
N
O
5.04
0.40
5.65
0.86
O
N
H
O
O
33-35, linked to the acetylene group were prepared by the dimerization shown in
Scheme 4. Only, 33 was synthesized by the structure of 21 via the coupling reaction of
quinazolone, 11 and propazyl bromide. Nitro reduction and coupling reaction with tripeptide
obtained the structure of 21 in the same methods as Scheme 3. The dimerized analogues were
prepared by TMEDA and CuCl2 and following Boc-deprotection gave the desirable structure
of 22.
8

R
X
N
H
N
R
X
N
N
N
b, c
a
O2N
O
O
12
N
O
O
O
NH
N
20
21
Boc
R
R
X
N
X
N
H
N
H
N
d, e
N
N
N
N
O
O
O
O
O
O
O
O
HN
NH
N
N
22
H
H
Scheme 4. Reagents and conditions: (a) Amine, iPrOH, 80 ℃, 4 h; (b) Fe, HCl, 50% EtOH,
reflux, 8 h; (c) EDCI, Pyridine, Tripeptide, 60 ℃, 4 h; (d) TMEDA, CuCl2, Acetone, 25 ℃, 6
h; (e) 4M HCl in Dioxane, 25 ℃, 4 h.
33 and 34 showed potential cellular activity of 0.20 nM and 0.30 nM, respectively,
but still showed strong inhibitory activity against CYP3A4. 35, which has a linker containing
pyridine, was shown to have the lowest activity. Table 2 summarized the antiproliferative and
inhibitory activities of 33-35 against MDA-MB-231 and CYP3A4.
Table 2. Diamine linked-derivatives 33-35 synthesized via Scheme 4
R
R
X
N
X
N
H
N
H
N
N
N
N
N
O
O
O
O
O
O
O
O
HN
NH
N
N
H
H
MDA-MB-231
CYP 3A4
(IC50, nM)
Compound
33
X
R
(IC50, nM)
CH2
O
0.20
0.24
CH2
34
35
NH
NH
0.30
34.6
-
-
O
N
9

To derive final candidate, 27 and 33 having good cellular activity were tested in CYP
isozyme and microsomal stability. In this assay, 27 showed moderate inhibition of CYP3A4
and weak 4 major CYP enzymes, whereas 33 strongly inhibited CYP3A4 (Table 3). These
results indicate that 27 has a lower risk of drug-drug interactions than 33. Moreover, 27 showed
good microsomal stability in all species than 33. (Table 4)
Table 3. in vitro evaluation of 27 and 33 in various CYP isozymes
CYP isozymes (IC50, μM)
Compound
CYP3A4
3.6
CYP1A2
CYP2C9
CYP2C19
CYP2D6
>50.0
N/I*
27
33
>50.0
43.6
35.7
0.24
>50.0
12.6
>50.0
*N/I; non-specific inhibition
Table 4. Microsomal stability of 27 and 33
Remaining % of Parent molecule at 60 min
Compound
Human
86
Dog
63
Rat
100
87
Mouse
94
27
34
64
65
62
Based on the cellular activity and CYP inhibition in the above screening data, 27 was
selected for further characterization. We evaluated the ability of 27 to restore the activity of
caspase-3 and caspase-9 inhibited by XIAP in MDA-MB-231 caspase assays. IC50 values of
test compound and Kd values of 27 was obtained, and Ki values of test compounds calculated
there from are shown in Table 5.
Table 5. XIAP-BIR3 binding affinity and caspase activation of 27
Compound
27
XIAP-BIR3 (Ki, nM)a
64.0
Caspase-9 Activation (Fold)b
Caspase-3 Activation (Fold)b
10.7
3.4
aRecombinant BIR3 domain (241-356) of human XIAP, bAssay Conc.; 1.0 nM in MDA-MB-231 Breast cancer cell.
27 was profiled for its antiproliferative activity across a number of cancer cell lines
10

representing a variety of tumor types (Table 6). Of the 8 cell lines examined, 4 cell lines were
sensitive as GI50 <1 nM and no activity to normal cell line, Hs27 (GI50 >10,000 nM).
Table 6. in vitro evaluation of 27 in selected tumor cell lines
Cell line
MDA-MB-468
MCF-7
Tumor Type
Breast
IC50, nM
27.8
19.2
0.2
Breast
OVCAR-3
Bx-PC3
Ovary
Pancreas
Pancreas
Pancreas
Bladder
Fibroblasts
0.2
Panc-1
0.9
MiaPaCa-2
J82
0.1
17.4
>10,000
Hs27
(a)
(b)
MDA-MB-231
Vehicle control
800
600
400
200
0
AEG40730, 3 mg/kg (iv)
27, 3 mg/kg (iv)
27 :
(nM)
0
1
2
5
XIAP
30
Cell viability :
98
67
42
cIAP-1
cIAP-2
γ-tubulin
0
3
6
9
12 15 18 21 24 27 30
Days
Figure 3. (a) 27 inhibited the growth of MDA-MB-231 human breast cancer xenografts model.
27 was administered i.v., during on D1-D14 (q1d) and AEG40730, 3 on D1-D6 (q1d); (b) The
inhibitory effect of 27 on IAP family member proteins, XIAP, cIAP1, and cIAP2. Cell lysates
were prepared and analyzed with anti-XIAP, cIAP-1, cIAP-2 and γ–tubulin antibodies
27 was evaluated using an MDA-MB-231 xenograft model compared to AEG40730,
3 (Fig. 3.a). At 3.0 mg/kg, i.v., q1d, 27 showed good potency without any body weight loss.
Moreover, 27 showed complete response (CR) in 4 of 5 and partial response (PR) in 1 of 5 in
tumor burdens, compared to the vehicle control. Unfortunately, intravenous injection of
AEG40730, 3 was stopped at day 6 because of inflammation occurrence around the injection
11

site after iv. dosing. Moreover, to study the effects of 27 on the IAP proteins, we tested 27 for
inhibition of the IAP family in MDA-MB-231 tumor tissue in vitro (Fig. 3.b). 27 had shown
degradation of XIAP, cIAP-1 and cIAP-2 of BIR3 domain in these tumors in a dose-dependent
manner, with full inhibition at in a low dose-concentration suggesting that 27 was potentially
inhibiting the IAP family XIAP, cIAP-1 and cIAP-2 both in vitro and in vivo.
In summary, we developed a synthesis of a novel series of SMAC mimetics using a
quinazoline-based structure. We found that introducing these bivalent derivatives provide
dramatically improved cellular potency, compared to monovalent 7 (HM90822). The
quinazoline scaffold showed good caspase activation at low concentration and a remarkable
cellular potency over a number of cancer cell lines on breast, pancreas, ovary, NSCLC,
leukemia. In the MDA-MB-231 xenograft model, 27 induces strong apoptosis in tumor tissues,
and the tumors completely regress with no obvious toxicity observed in normal mouse tissues.
More detailed and dose-dependent studies on PK, ADME, efficacy and toxicity of 27 will be
explored in the future.
Acknowledgments
We are grateful to Y. A. Seo, D. H. Jin and T. W. Kim for useful discussions and
critical reading of the manuscript. We thank the Pharmacology Team at Hanmi Research
Center for cell line screening and evaluation of efficacy study.
Declarations of interest: none.
Funding: not applicable
Supplementary data
Supplementary data associated with this article can be found in the online version at
12

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