Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective Indoleamine-2,3-dioxygenase 1 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.0c00443

In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13-15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.

Full text of DOI:10.1021/acsmedchemlett.0c00443

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Letter
Discovery of Hydroxyamidine Derivatives as Highly Potent, Selective
Indoleamine-2,3-dioxygenase 1 Inhibitors
Fangfang Jin,* Qiyue Hu, Hongbo Fei, Hejun Lv, Shenglan Wang, Bin Gui, Junzhen Zhang,
Wangyang Tu, Yun Zhang, Lei Zhang, Hong Wan, Limin Zhang, Bin Hu, Fanglong Yang, Chang Bai,
Feng He, Lianshan Zhang, and Weikang Tao
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ABSTRACT: In this study, a series of novel hydroxyamidine
derivatives were identified as potent and selective IDO1 inhibitors
by structure-based drug design. Among them, compounds 13−15
and 18 exhibited favorable enzymatic and cellular activities.
Compound 18 showed improved bioavailability in mouse, rat,
and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable
in vivo pharmacokinetic properties, compound 18 was further
evaluated in a transgenic MC38 xenograft mouse model. The
combination of compound 18 with PD-1 monoclonal antibody
showed a synergistic antitumor effect. These data indicated that
compound 18 as a potential cancer immunotherapy agent should
warrant further investigation.
KEYWORDS: IDO1, cancer immunotherapy, hydroxyamidine derivatives, lead optimization, structure-based drug design, bioisostere
ver the past two decades, immunotherapy has been
Otransformed into a mainstream treatment method with
great potential for a variety of cancers.1 However, there are
occasions where the immune system cannot effectively control
the development of tumors due to immune tolerance.
Indoleamine 2,3-dioxygenase 1 (IDO1), an immune regulatory
enzyme, plays an important role in regulating the immune
system through the control of the kynerenine pathway.2−4
IDO1 is a heme-containing monomeric enzyme that
controls the rate-limiting step of catabolizing tryptophan to
N-kynurenine along the kynurenine pathway, which is
responsible for local immunosuppression.5−7 Plenty of studies
indicate that the abnormal expression of IDO1 is related to
tumor cells evading the immune system. IDO1 can oxidize and
destroy tryptophan, which is an important amino acid for T
cell activation. In this way, T cells lose the ability to kill tumors.
In principle, blocking IDO1 can active T-cells and promote the
immune system to kill cancer cells. Therefore, IDO1 is an
attractive target for cancer immunotherapy.8
Epacadostat (INCB-24360) is developed as a selective IDO1
inhibitor. It has been used with checkpoint modulators for
cancer treatment in clinical studies and showed an early sign of
benefit in phase I/II trials.9−11 However, epacadostat in
combination with pembrolizumab in the ECHO-301 phase III
trial has failed to increase the overall and progression-free
survival when compared to pembrolizumab alone.12 The
disappointing phase III results have cooled down the research
interest in the IDO1 inhibitors. However, IDO1 related
therapy is still a promising field, as evidenced by multiple
ongoing clinical trials from several companies.13,14 For
example, an IDO1 inhibitor from Bristol-Myers Squibb,
BMS-986205, is currently in an active phase 3 trial in Muscle
Invasive Bladder Cancer (MIBC).15
The crystal structure of IDO1 in complex with epacadostat
was published in 2018 with a PDB entry of 6E40,16 which
opens the door for structure-based design of novel IDO1
inhibitors. In this crystal structure, epacadostat is positioned in
the active pocket by three key contacts: (1) a π−π interaction
between its substituted phenyl ring and the residue Tyr126;
(2) a hydrogen bond formed by sulfamide and Arg231; (3) a
dative bond formed between the N-hydroxylamidine oxygen
and the heme iron (Figure 1). The furazan ring is often found
in pyrotechnic compounds and propellants but is rarely used in
medicines.17 Up to now, most medchem efforts have been
focused on optimizing the hydroxyamidine motifs as well as
the halogenated phenyl region.18−22 The sulfamide side chain
and core modification especially the furazan ring replacement
remain to be explored. So, herein, we describe our work that
Received: August 14, 2020
Accepted: January 15, 2021
Published: January 20, 2021
https://dx.doi.org/10.1021/acsmedchemlett.0c00443
© 2021 American Chemical Society
ACS Med. Chem. Lett. 2021, 12, 195−201
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compounds were calculated; these are shown in Table 1.
The calculated pKa values showed some correlation with the
enzymatic activity. All the activities were similar to that of the
reference compound except compound 3 which might be due
to suboptimal binding reflected in the weaker docking score.
Based on the enzymatic and cellular data, as well as the
calculated pKa, compound 5 was selected as the starting point
for the next round SAR study. A series of cyclohexane
substitutions were designed and synthesized (Table 2,
compounds 7−10, Schemes S7−S10), none of them showed
improved enzymatic potency. As inspired by our previous
work,26 substituted piperidinyls were investigated (Table 2).
Weak electron-withdrawing substitutions such as benzene
(compound 11, Scheme S11) and benzaldehyde (compound
12, Scheme S12) showed similar potencies in IDO1 enzymatic
assays as compound 5, with reduced cellular potencies.
Interestingly, the phenylformamide substitution (compound
13, Scheme S13) showed 3-fold increase in the enzymatic
potency compared to compound 5. Further substitution at the
para-position with 1-methylpyrazol-4-yl (compound 14,
Scheme S14) resulted in a 10-fold and a 4-fold increase in
the enzymatic and cellular potencies, respectively. The
benzylformamide substitution (compound 15, Scheme S15)
and the sulfonyl substitution (compound 18, Scheme 1)
showed similar potency levels in both enzymatic and cellular
assays as compound 14.
To further analyze binding poses of the designed
compounds, we also performed molecular modeling studies
on compound 14 and 18. As shown in Figure 2, both
compounds shared a similar binding pose in the pocket A. As a
result, the deprotonated oxygen of the N-hydroxylamidine was
positioned to bind the heme iron similarly as epacadostat. In
the pocket B, compound 18 formed the aformentioned
hydrogen bond with the residue Arg231 (Figure 2B).
Interestingly, a significant cation−π interaction was formed
at a distance of 2.47 Å between the Arg231 and the phenyl
group in compound 14 (Figure 2A). Cation−π interactions
were quite common in proteins, protein−ligands and protein−
DNA complexes, and important for protein folding, molecular
recognition and catalysis.29 Thus, it was reasonable to expect
that the similar cation-π interactions in the pocket B could
contribute to the improvement of binding potencies in
compounds, 13−16.
To further evaluate the ADMET properties of compounds
13−15 and 18, we profiled them in CYP and hERG inhibition
assays. As shown in Table S2, all the compounds except 15 had
clean CYP and hERG profiles. In addition to compound 18, we
selected the most potent compound 14 for further in vivo
studies among the compounds forming cation−π interactions.
Two animal models (rat and dog) were used to evaluate the
pharmacokinetics of those two compounds. As listed in Table
3, compound 14 showed poor oral pharmacokinetics in dog,
while compound 18 had a better profile and good oral
exposure in both species.
The synthesis route and in vitro and in vivo Profile for
compound 18 are shown in Scheme 1 and Table 4. In vitro
data indicated that compound 18 was a highly potent and
selective IDO1 inhibitor with clean CYP and hERG profiles. Its
pharmacokinetic profiles in animal models (mouse, rat, and
dog) demonstrated an increased oral exposure and bioavail-
ability from mouse, rat, to dog (F = 44%, 58%, and 102.1%,
respectively). Meanwhile, compared with epacadostat, com-
pound 18 exhibited a superior pharmacokinetic profile in a
Figure 1. (A) Hydroxyamidine derivative as IDO1 inhibitor; (B)
INCB-24360 (navy) binding mode in the crystal structure (PDB
6E40).
has led to the identification of novel IDO1 inhibitors by
bioisosteric replacements of the furazan group, as well as the
alternative groups to the sulfamide side chain.
We designed a set of electron-withdrawing carbonyl groups
to replace the furazan ring (compounds 1−6; the synthesis
route of compounds 1−6 is shown in Schemes S1−S6), aiming
to keep the acidity of the hydroxylamidine group. Sub-
sequently, biological assays were employed to evaluate the
biological activities of compounds 1−6, including enzymatic
assays with purified recombinant human IDO1/TDO proteins
and cellular IDO1 inhibition assays using HeLa cell lines. As
shown in Table 1, compound 1 with thiazole substitution
exhibited the best enzymatic activity (IDO1 IC50 = 51 nM)
among those designs. It showed micromolar level activity in
the HeLa cell line, which could be related to the membrane
permeability of the compound. Compounds 2−4 with
aromatic or heterocyclic aromatic substitutions also showed
less potencies compared to epacadostat in enzymatic and
cellular assays. Compound 5 with saturated six-member ring
showed a modest enzymatic activity, and the best cellular
activity among the designed compounds. As shown by the
structure−activity relationship (SAR) data of compound 6, the
carbonyl group of compound 5 was quite important for its
enzymatic and cellular potencies.
A molecular modeling study was carried out to further
understand the SAR of these compounds. It was well-known
that the interaction between the deprotonated oxygen and the
heme iron is important for biological activity.18,19 So we
hypothesized that the oxygen of the N-hydroxyamidine was in
the deprotonated state and the heme iron was in its ferrous
state (Fe2+). Compounds 1−6 were docked into the binding
pocket using MOE.23,24 A commonly used docking score in
MOE, GBVI/WSA dG28 alone, could not be used to
distinguish actives from inactives (Table 1). Then, the pKa
values25 of the heme interaction oxygens from each
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Table 1. SAR of the Furazan Ring Replacement Groups with Charge and pKa Data
a
b
Values are expressed as the mean of at least two independent determinations. pKa was calculated using JChem For Excel.27,28
nonrodent species (dog) with lower clearance and better
bioavailability. Compound 18 had the potential to show better
pharmacokinetic profile in humans than epacadostat.
To further understand the mechanism of action, the in vivo
pharmacodynamics (PD) study of compound 18 was carried
out in a mouse model. After administrated orally to C57 mice
(300 mg/kg single dose), compound 18 was able to reduce the
level of kynurenine down to 87.8% at 2 h after dosing (Figure
3). The concentration change of kynurenine was proportional
to the exposure level of the compound.
The antitumor effects of compound 18 in combination with
PD-1 antibody were further evaluated using the MC38 tumor
growth inhibition model in hPD-1 transgenic mice. Due to the
lower exposure seen in mice, higher doses of compound 18
were used to match the exposure level of epacadostat. As
shown in Figure 4, Oral treatment of compound 18 combined
with PD-1 antibody (PD-1, 3 mg/kg, ip, qod ×8; compound
18, 300 or 600 mg/kg, po, bid ×14) showed good dose-
dependent tumor growth inhibition (150 mg/kg, TGI =
60.3%; 300 mg/kg, TGI = 71.7%; 600 mg/kg, TGI = 86.8%).
The PD-1 combo treatment groups with 300 or 600 mg/kg
compound 18 showed better antitumor efficacy compared to
either PD-1 alone (3 mg/kg, ip, qod ×8, TGI = 57.3%) or the
combination usage of epacadostat and PD-1 (PD-1, 3 mg/kg,
ip, qod ×8; epacadostat, 100 mg/kg, po bid ×14, TGI =
66.9%). No body weight losses were observed in all the
treatment groups.
In summary, we developed a series of novel hydroxyamidine
based IDO1 inhibitors using the structure-based drug design
approach. Among these derivatives, compounds 14 and 18
showed favorable enzymatic and cellular activities against
IDO1, which indicated that the carbonyl group could be used
as a bioisostere replacement for the furazan ring in drug design.
As compound 14 showed a poor dog PK, further in vivo
studies were focused on compound 18. In the transgenic
MC38 xenograft model, compound 18 was orally efficacious in
combination with PD-1 monoclonal antibody and showed a
synergistic antitumor effect. Together with the increased
bioavailability from rodent to larger nonrodent animals, these
in vivo PD and efficacy studies demonstrated that compound
18 warrant further investigation as a potential add-on cancer
immunotherapy agent to PD-1 antibody.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00443.
Biological assays, pharmacokinetic assays, in vivo efficacy
study, experimental procedures, and analytical data for
compound 18 (PDF)
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Letter
a
Table 2. Structure−Activity Relationship Data of
Cyclohexane and Piperidine Substituted Hydroxylamidine
Scheme 1. Synthesis of Compound 18
a
Reagents and conditions: (a) SeO2, 1,4-dioxane, 80 °C, 16 h; (b)
NH2OH·HCl, K2CO3, CH3OH, rt, 2 h; (c) NCS, DMF, rt, 16 h; (d)
3-bromo-4-fluoroaniline, EtOH, rt, 3 h; (e) 4 M HCl in 1,4-dioxane, 2
h; (f) tert-butyl chlorosulfonylcarbamate, Et3N, DCM, 0 °C, 1 h; (g) 4
M HCl in 1,4-dioxane, MeOH, rt, 1 h.
Figure 2. Molecular docking of active compounds binding to the
IDO1 active site (PDB code: 6E40). (A) Compound 14 (cyan); (B)
compound 18 (purple).
a
Values are expressed as the mean of at least two independent
determinations.
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Table 3. Oral Pharmacokinetic Profiles of Compound 14
and 18
rat PK@3mg/kg
AUC
dog PK@2mg/kg
AUC
Cmax
t1/2
(h)
Cmax
t1/2
(h)
compd (ng/mL) (ng/mL·h)
(ng/mL) (ng/mL·h)
14
18
173
179
1034
1527
5.08
6.14
140
742
255
3633
1.10
3.04
Table 4. Profiling of Compound 18
INCB-24360
(epacadostat)
assay
18
enzymatic IDO1 IC50 (nM)
enzymatic TDO IC50 (nM)
cellular HeLa IC50 (nM)
63
62 457
45
26
>10 000
5.3
CYP inhibition (1A2, 2C9, 2C19,
2D6, 3A4)
>10uM
>10uM
hERG
>30 uM
>30 uM
PPB (rat/dog/human)
92.4%/96.0%/
96.4%
93.4/348.7
97.0%/97.5%/
98.5%
73.1/293
Figure 4. Efficacy study of compound 18 in combination with PD-1
monoclonal antibody in the MC38 xenograft model in hPD-1
transgenic mice.
liver microsome stability (rat/
human) T1/2 (min)
mouse PK@3mg/kg
Cmax (ng/mL)
AUC (ng/mL·h)
t1/2 (h)
Cl (μL/min/mg)
bioavailability (F%)
rat PK@3mg/kg
Cmax (ng/mL)
AUC (ng/mL·h)
t1/2 (h)
Cl (μL/min/mg)
bioavailability (F%)
dog PK@2mg/kg
Cmax (ng/mL)
AUC (ng/mL·h)
t1/2 (h)
127
358
1.21
61.2
44%
253
AUTHOR INFORMATION
Corresponding Author
■
1016
2.41
49.2
44%
Fangfang Jin − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China; orcid.org/0000-0002-8983-
2529; Email: jinff@shhrp.com
Authors
179
133
807
2.73
29
Qiyue Hu − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Hongbo Fei − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Hejun Lv − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Shenglan Wang − Shanghai Hengrui Pharmaceutical Co.,
Ltd., Shanghai 200245, China
1527
6.14
16.7
58.8%
55%
742
245
676
5.03
36.6
50%
3633
3.04
9.3
Cl (μL/min/mg)
bioavailability (F%)
Bin Gui − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
102.1%
Junzhen Zhang − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Wangyang Tu − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Yun Zhang − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Lei Zhang − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Hong Wan − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Limin Zhang − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Bin Hu − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Fanglong Yang − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China
Chang Bai − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China; Chengdu Suncadia Medicine Co.,
Ltd., Chengdu, Sichuan 610000, China
Figure 3. Kynurenine reduction of oral administration of compound
18 in the C57 mouse model.
Feng He − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China; Chengdu Suncadia Medicine Co.,
Ltd., Chengdu, Sichuan 610000, China
Lianshan Zhang − Jiangsu Hengrui Medicine Co., Ltd.,
Lianyungang, Jiangsu 222047, China
199
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Letter
Patients with Advanced Solid Malignancies. Clin. Cancer Res. 2017,
23, 3269−3276.
Weikang Tao − Shanghai Hengrui Pharmaceutical Co., Ltd.,
Shanghai 200245, China; Chengdu Suncadia Medicine Co.,
Ltd., Chengdu, Sichuan 610000, China
(10) Kristeleit, R.; Davidenko, I.; Shirinkin, V.; El-Khouly, F.;
Bondarenko, I.; Goodheart, M. J.; Gorbunova, V.; Penning, C. A.; Shi,
J. G.; Liu, X.; Newton, R. C.; Zhao, Y.; Maleski, J.; Leopold, L.;
Schilder, R. J. A Randomised, Open-Label, Phase 2 Study of the IDO1
Inhibitor Epacadostat (INCB024360) versus Tamoxifen as Therapy
for Biochemically Recurrent (CA-125 Relapse)−Only Epithelial
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.0c00443
Author Contributions
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
(11) Komiya, T.; Huang, C. H. Updates in the Clinical Development
of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors
(IDO1) for Human Cancers. Front. Oncol. 2018, 8, 423.
(12) Long, G. V.; Dummer, R.; Hamid, O.; Gajewski, T. F.;
Caglevic, C.; Dalle, S.; Arance, A.; Carlino, M. S.; Grob, J.-J.; Kim, T.
M.; Demidov, L.; Robert, C.; Larkin, J.; Anderson, J. R.; Maleski, J.;
Jones, M.; Diede, S. J.; Mitchell, T. C. Epacadostat plus
Pembrolizumab versus Placebo plus Pembrolizumab in Patients
with Unresectable or Metastatic Melanoma (ECHO-301/KEYNOTE-
252): A Phase 3, Randomised, Double-Blind Study. Lancet Oncol.
2019, 20, 1083−1097.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Wang Jingfang for proof reading the manuscript and
Chen Yiqian, Jiang Hongjian, Qin Qiang, Xu Anchao, Zhang
Baolei, Yuan Jijun, Wang Dan, Mao Yuchang, Zhu Ying, Feng
Jun, Wang Qian, Yang Changyong, Fan Yuanmin, and Liu
Xiaolan for their contributions to the project.
(13) Neoadjuvant Celecoxib in Newly Diagnosed Patients With
Endometrial Carcinoma. ClinicalTrials.gov, 2019. DOI: 10.31525/ct1-
nct03896113.
ABBREVIATIONS
■
IDO1, Indoleamine 2, 3-dioxygenase 1; TDO1, tryptophan
2,3-dioxygenase 1; MOE, Molecular Operating Environment;
PD-1, programmed death 1; DMHH, N,O-dimethylhydroxyl-
amine hydrochloride; DMAP, 4-dimethylaminopyridine;
DCM, dichloromethane; NCS, N-chlorosuccinimide; EDC,
3-(ethyliminomethylideneamino)-N,N-dimethylpropan-1-
amine; THF, tetrahydrofuran; DMF, dimethylformamide;
SAR, structure−activity relationship; CYP, cytochrome p450
enzyme; hERG, human ether-a-go-go-related gene; PPB,
plasma protein bonding; PK, pharmacokinetic; po, orally; ip,
intraperitoneally; bid, twice daily; qod, every other day; TGI,
tumor growth inhibition.
(14) Luke, J. J.; Tabernero, J.; Joshua, A.; Desai, J.; Varga, A. I.;
Moreno, V.; Gomez-Roca, C. A.; Markman, B.; De Braud, F. G.; Patel,
S. P.; Carlino, M. S.; Siu, L. L.; Curigliano, G.; Liu, Z.; Ishii, Y.; Wind-
Rotolo, M.; Basciano, P. A.; Azrilevich, A.; Gelmon, K. A. BMS-
986205, an Indoleamine 2, 3-Dioxygenase 1 Inhibitor (IDO1), in
Combination with Nivolumab (Nivo): Updated Safety across All
Tumor Cohorts and Efficacy in Advanced Bladder Cancer (AdvBC).
J. Clin. Oncol. 2019, 37, 358.
(15) Sonpavde, G.; Necchi, A.; Gupta, S.; Steinberg, G. D.;
Gschwend, J. E.; Van Der Heijden, M. S.; Garzon, N.; Elegbe, A.;
Raybold, B.; Liaw, D.; Rutstein, M.; Galsky, M. D. A Phase 3
Randomized Study of Neoadjuvant Chemotherapy (NAC) Alone or
in Combination with Nivolumab (NIVO)
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Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC). J. Clin.
Oncol. 2019, 37, TPS4587.
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