Conformational-Analysis-Guided Discovery of 2,3-Disubstituted Pyridine IDO1 Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.1c00236

IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1 inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that, while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound 29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.

Full text of DOI:10.1021/acsmedchemlett.1c00236

pubs.acs.org/acsmedchemlett
Letter
Conformational-Analysis-Guided Discovery of 2,3-Disubstituted
Pyridine IDO1 Inhibitors
Emily C. Cherney,* Liping Zhang, Weiwei Guo, Audris Huang, David Williams, Steven Seitz,
Weifang Shan, Xiao Zhu, Johnni Gullo-Brown, Derrick Maley, Tai-an Lin, John T. Hunt,
Christine Huang, Zheng Yang, Celia J. D’Arienzo, Lorell N. Discenza, Asoka Ranasinghe, Mary F. Grubb,
Sarah C. Traeger, Xin Li, Kathy A. Johnston, Lisa Kopcho, Mark Fereshteh, Kimberly A. Foster,
Kevin Stefanski, Diane Delpy, Gopal Dhar, Aravind Anandam, Sandeep Mahankali,
Shweta Padmanabhan, Prabhakar Rajanna, Venkata Murali, T. Thanga Mariappan, Shabeerali Pattasseri,
Roshan Y. Nimje, Zhenqiu Hong, James Kempson, Richard Rampulla, Arvind Mathur, Anuradha Gupta,
Robert Borzilleri, Gregory Vite, and Aaron Balog
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sı Supporting Information
ABSTRACT: IDO1 inhibitors have shown promise as immunotherapies for the treatment of a variety of cancers, including
metastatic melanoma and renal cell carcinoma. We recently reported the identification of several novel heme-displacing IDO1
inhibitors, including the clinical molecules linrodostat (BMS-986205) and BMS-986242. Both molecules contain quinolines that,
while being present in successful medicines, are known to be potentially susceptible to oxidative metabolism. Efforts to swap this
quinoline with an alternative aromatic system led to the discovery of 2,3-disubstituted pyridines as suitable replacements. Further
optimization, which included lowering ClogP in combination with strategic fluorine incorporation, led to the discovery of compound
29, a potent, selective IDO1 inhibitor with robust pharmacodynamic activity in a mouse xenograft model.
KEYWORDS: Indoleamine 2,3-dioxygenase, IDO1, immuno-oncology, cancer immunotherapy, quinoline, metabolism
ver the past several decades, the immune system’s role in
cancer recognition and killing has been a source of debate.
TME. Preclinically, IDO1 inhibition has been shown to work
synergistically with both conventional cancer therapies and
O
4
−6
In recent years, as mechanisms of tumoral immune escape have
been elucidated and proven in the clinic with checkpoint
inhibitors such as Opdivo, Keytruda, and Yervoy, the field has
checkpoint immunotherapy.
This combination of attributes
makes IDO1 a promising target for cancer immunotherapy.
IDO1 catalyzes the oxidative cleavage of the 2,3-double bond
in D- or L-tryptophan. This oxidative cleavage event is the initial
and rate-limiting step of tryptophan catabolism. IDO1 is a
monomeric heme-containing dioxygenase, meaning that both
atoms of molecular oxygen are incorporated into the
1
gained mainstream acceptance. Further understanding of the
impact of amino acid metabolism on the tumor microenviron-
ment (TME) has led to the identification of immuno-oncology
2
(
IO) targets capable of small-molecule perturbation. One such
target, indoleamine 2,3-dioxygenase-1 (IDO1), is a cytosolic
enzyme expressed in tumors and tumor-associated cells such as
dendritic cells (DCs) and endothelial cells. High IDO1
expression in the tumor or tumor-draining lymph nodes has
Received: April 21, 2021
Accepted: June 11, 2021
Published: June 16, 2021
3
been associated with poor prognosis. Checkpoint inhibitors
activate T cells within the tumor and cause antitumor
inflammation, which can increase IDO1 expression in the
©
2021 American Chemical Society
https://doi.org/10.1021/acsmedchemlett.1c00236
1
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tryptophan-derived oxidative cleavage product, N-formylkynur-
enine, which can then undergo deformylation with kynurenine
7
formamidase to form kynurenine. The closely related enzymes
IDO2 and tryptophan 2,3-dioxygenase (TDO) are also capable
of effecting this transformation. The physiological role of IDO2
has not been fully elucidated, and although it is primarily
expressed in hepatocytes, it is not critical for systemic
8
tryptophan homeostasis, as is the case with TDO. IDO2
possesses only 43% sequence homology with IDO1 and weaker
9
affinity for L-tryptophan. TDO (sometimes called TDO2) is
tetrameric as opposed to monomeric, enantiospecific for the
catabolism of L-tryptophan, and expressed mainly in the
1
0,11
liver.
TDO is primarily responsible for maintaining
homeostasis of dietary L-tryptophan, suggesting a role distinct
12
from that of IDO1.
IDO1 expression can be induced in a variety of ways,
including type I and type II interferons (including IFNγ),
reverse signaling from inhibitory T cell receptors such as binding
13
of CTLA4 to CD80, and COX-2 via PGE2 production. High
levels of IDO1 expression in the TME lead to localized L-Trp
depletion and high kynurenine levels. Low L-Trp levels can
activate stress response kinase GCN2, leading to biased
̈
differentiation of naive T cells into regulatory T (T ) cells, T
reg
4,15
1
cell anergy, and inhibition of T cell proliferation.
Addition-
ally, activation of GCN2 can alter DCs to a more
immunosuppressive phenotype that produces TGFβ and IL-
1
6
1
0. Kynurenine can activate the aryl hydrocarbon receptor
AhR) upon binding, which can also cause differentiation of
(
Figure 1. (a) IDO1 inhibitors either clinically investigated by Bristol
Myers Squibb (1, 2) or crystallized with hIDO1 protein (3). (b) X-ray
cocrystal of human IDO1 and compound 3 (in green), a closely related
analogue of linrodostat (1). Heme (in orange) has been added to show
that 3 occupies the heme binding pocket.
̈
naive T cells into T cells and lead to the formation of
reg
17
immunosuppressive DCs. These myriad effector pathways can
18
ultimately lead to immune tolerance toward tumoral antigens.
Encouraged by the promising preclinical and clinical data
available for IDO1, many companies targeted small-molecule
inhibitors for cancer immunotherapy. Several candidates have
entered the clinic in combination with chemotherapy, vaccines,
energy analysis was used to prioritize compounds biased to
28
reside in an active conformation.
19
and checkpoint immunotherapy. More specifically, Bristol
Docking studies showed that both cis-cyclohexanes in
conformer I (the cocrystal conformer of 3) and trans-
cyclohexanes in conformer III were predicted to bind well
20
Myers Squibb advanced linrodostat (1) and closely related
2
1
BMS-986242 (2) into clinical studies (Figure 1a). The unique
binding mode of these inhibitors to apo-IDO1 (3 in Figure 1)
(
see Figure 2). Modeling also predicted that cis-cyclohexanes in
22,23
and mechanistic studies were previously disclosed.
conformer II and trans-cyclohexanes in conformer IV would not
bind. We worried that replacing the cis-cyclohexylquinoline in 3
While our (and others’) initial efforts toward identifying an
IDO1 inhibitor that was differentiated from 1 focused primarily
on structure−activity relationship (SAR) exploration in the
21,24a,c
amide portion of the molecule,
we subsequently sought to
modify the quinoline present in both 1 and 2. Quinolines, while
25
found in many marketed drugs, including antimalarials and
2
6
27
anticancer drugs, are known sites of metabolic activation.
Indeed, in vitro biotransformation studies of 2 in hepatocytes of
preclinical species revealed that the quinoline was susceptible to
metabolic oxidation. For this reason, efforts were initiated to
improve the metabolic stability of this chemotype by either
adding electron-withdrawing groups to the quinoline to reduce
24a
the N-oxidation potential
or replacing it entirely while
simultaneously lowering the lipophilicity, which is the focus of
this work.
Quinoline replacements were designed to maintain the π-
stacking interaction with Phe270 and probe whether hydrogen
bonding with Arg343 was necessary (Figure 1b). Additionally,
computer-aided drug design (CADD) conformational studies
revealed that the dihedral angle between the quinoline and the
cyclohexane in the X-ray cocrystal of 3 resided very close to the
dihedral angle of the calculated solution-state intrinsic torsional
energy minimum. During analogue design, intrinsic torsional
Figure 2. Potential chair conformational isomers of cis- and trans-
cyclohexane analogues: conformers I and III bind to hIDO1 in a
docking model, whereas conformers II and IV do not.
1
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Letter
a
Scheme 1. General Synthetic Scheme for Compounds 14−25 and 27−29
a
Reagents and conditions: (a) NaH, THF, 0 °C (H = 96% yield, Me = 78% yield); (b) Pd−C, MeOH, H (balloon to 50 PSI) (H = 98% yield, Me
2
=
89% yield); (c) 4 N HCl, acetone, 45 °C (H = 73% yield, Me = 79% yield); (d) NaHMDS (2 M in THF), N-phenyltrifluoromethanesulfonimide,
MTBE, −78 °C (H = 76% yield, Me = 96% yield); (e) B Pin , KOAc, NaBr, Pd(dppf)Cl , dioxane, 110 °C (H = 50% yield, Me = 60% yield); (f)
2
2
2
LDA, DMPU; EtI, −78 °C (95% yield); (g) LDA, MOMCl, −78 °C (61% yield); (h) Pd(PPh ) , K CO , dioxane, H O, 100 °C (27−99% yield);
3
4
2
3
2
(
i) Pd−C, MeOH, HCOONH , 80 °C or Pd−C, MeOH, H (30−99% yield); (j) LiOH, H O, THF, 70 °C, 72 h (58% to ca. quant. yield); (k)
4
2
2
DPPA, TEA, toluene, 70 °C; LiOH, THF (51−78% yield); (l) EDCI, HOBt, DIPEA, DMF, rt or HATU, DIPEA, DMF (3−39% yield).
Table 1. Quinoline Replacements: Broad Structure−Activity Relationships and Metabolic Stability
a
b
Data are reported as averages of ≥2 test results. See the Supporting Information for a description of the assay conditions. Percentage of the
c
1
parent compound (0.5 μM) remaining after a 10 min incubation with 1 mg/mL HLM or MLM. The absolute stereochemistry of R is R.
1
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Letter
Table 2. 2,3-Disubstituted Pyridines as Quinoline Replacements
a
b
Data are reported as averages of ≥3 test results. See the Supporting Information for a description of the assay conditions. Data are reported as
c
averages of ≥2 test results. See the Supporting Information for a description of the assay conditions. Percentage of the parent compound (0.5 μM)
remaining after a 10 min incubation with 1 mg/mL HLM, RLM, or MLM.
with smaller aryl groups could bias new analogues toward
disfavored conformer II. We were also wary of only targeting cis-
cyclohexanes and potentially overlooking active trans-cyclo-
hexanes, which have a strong energetic bias to reside in
conformer III. Therefore, both cis- and trans-cyclohexanes were
pursued simultaneously via a stereodivergent route during initial
SAR exploration (Scheme 1).
1. On the basis of intrinsic torsional energy analysis, aromatic or
heteroaromatic rings containing substitution at positions either
ortho or meta to the cyclohexyl ring were prioritized. Pyridone
13 and benzodioxole 14 were prioritized on the basis of this
strategy. Interestingly, compounds 13 and 14 maintained
double-digit nanomolar activity in human cellular assays without
containing a hydrogen-bond acceptor to interact with Arg343.
Unfortunately, both were significantly less potent than BMS-
986242 (2), and 14 suffered from very poor metabolic stability.
Contrary to our original hypothesis, para-substituted arene 15
demonstrated that neither ortho nor meta substitution is
required to maintain double-digit nanomolar human IDO1
potency. Also, the trans isomer of 15 was superior to the cis
isomer (data not shown). This trans preference was observed in
several compounds where ortho substitution was absent (15, 16,
17, 19, and 20), which could be due to a preference for cis
isomers with these aryl groups to adopt putatively disfavored
conformer II (Figure 2). Compound 21 was an exception to this
trend, perhaps because the 4-pyridyl nitrogen can interact with
Arg343 to bias 21 to adopt conformer I in the binding pocket.
Conversely, when ortho substitution was present, the cis isomer
was usually preferred (compounds 14, 18, 22, and 23), which
could be due to a preference for these aryl groups to adopt
known active conformer I (Figure 2). 4-Pyridyl compounds such
as 21, 22, and 23 not only had torsional energy minima
corresponding to the active conformation of the quinoline but
also retained the nitrogen to potentially interact with Arg343. As
expected, 21, 22, and 23 were more potent in cellular assays,
with 22 and 23 achieving single-digit nanomolar activity.
However, they suffered from very poor metabolic stability.
Our focus then turned to improving the metabolic stability of
the 4-pyridyl analogues (Table 2). Analogue 24, with 2-fluoro in
place of the 2-methyl group in 23, performed in the same fashion
as 23, displaying poor metabolic stability. However, swapping
for a 2-methoxy group (25) led to a significant improvement in
not only human whole-blood activity but also metabolic
Compounds 13−24 and 27−29 can be synthesized as
mixtures of diastereomers from intermediate 7a or 7b starting
from cyclohexanedione monoketal 4 following a previously
29
reported five-step sequence. Horner−Wadsworth−Emmons
olefination followed by reduction and ketal hydrolysis gave
ketones 6a or 6b. Formation of the vinyl triflate followed by
Miyaura borylation provided 7a or 7b. For 7c or 7d, 7a was
alkylated with either ethyl iodide or methoxylmethyl chloride,
respectively. Aryl halides could be installed via Suzuki coupling
to give 8a−c. Reduction of the styrenyl olefin via transfer
hydrogenation led to a mixture of cis and trans diastereomers. In
some cases, diastereomers were separated at this point.
Hydrolysis of the ester yielded acids 9a−c. Curtius rearrange-
ment provided amines 10a−c, which were then coupled to the
necessary acids to give compounds 13−24 and 27−29 as
mixtures of four diastereomers. For the final compounds 25 and
26, an additional displacement with sodium methoxide was
performed on advanced intermediates to provide 2-methox-
ypyridines (see the Supporting Information). For each of the
final compounds reported, chiral resolution was performed, and
the most potent enantiomer is reported in Tables 1 and 2. While
absolute stereochemistry was not routinely determined, 2D
NMR techniques were employed to assign relative cis/trans
stereochemistry for all of the final compounds (see the
Supporting Information).
As stated above, while absolute stereochemistry was not
routinely determined, all of the mixtures were chirally resolved,
and the relative stereochemistry was assigned by 2D NMR
analysis. The most potent enantiomer is reported below in Table
1
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Letter
stability. The 3-methyl group in 25 was a potential metabolic
soft spot, so it was replaced with a fluorine (26) or a
difluoromethyl group (27) in an attempt to bolster the
Table 4. PK−PD study of Compound 29 vs Linrodostat in a
Human SKOV3 Xenograft Tumor Mouse Model
a
b
c
30
cmpd
dose (mg/kg)
PK
PD (%)
metabolic stability. Gratifyingly, 27 with the difluoromethyl
group performed comparably to 25 in cellular and whole-blood
assays with further improved metabolic stability. Attempts to
introduce more polarity into the molecule and lower ClogP to
improve the metabolic stability included adding a MOM group
c
29
29
29
29
1
20
7.9
9.2
13
13
18
58
57
63
80
65
c
60
c
120
c
180
c
1
3
60
at R (28) and a methoxypyridine at R (29). SAR around the
a
b
amide portion of the molecule has been discussed in greater
QD po dosing. PK is AUC (0−24 h) in μM·h measured in the
21,24
c
tumor. PD is percent kynurenine AUEC (0−24 h) reduction
measured in the tumor. %Kyn reduction was measured at steady state
after the fifth dose (calculated as the area under the Kyn
concentration−time curve from 0 to 24 h) and compared with that
of the vehicle control.
detail previously.
Modification of the cyclohexyl core to
more polar, saturated heterocycles (not shown) did not yield
superior leads. While the MOM group in 28 was unsuccessful in
improving the metabolic stability, methoxypyridine-containing
29 showed an overall superior profile in terms of human cellular
and whole-blood potency as well as metabolic stability across
species. Compound 29 has a lower ClogP than prior candidates
to lower protein binding (vide supra). While the 180 mg/kg dose
displays a deeper PD effect (80% reduction), it is unclear why
the 120 mg/kg dose, despite reaching similar exposure in the
tumor, reached only 63% kynurenine reduction. Pharmacoki-
netic studies in preclinical species (Table 5) showed moderate
1
and 2 (6.39 for 1 vs 5.94 for 2 vs 4.46 for 29) and other closely
related analogues shown in Table 2.
The relative stereochemistry around the cyclohexane in 29
was confirmed to be cis via 2D NMR experiments. The absolute
1
stereochemistry at R was confirmed to be R, which is consistent
Table 5. PK Parameters for Compound 29
with the stereochemistry in 1 and 2 (see the structure in Table
3
1
a
a
a
e
a
3
). Further in vitro profiling revealed that lower ClogP
parameter
mouse
rat
b
dog
cyno
b
c
c
d
d
e
dose (mg/kg) iv/po
CL (mL/min/kg) iv
Vss (L/kg) iv
1 /10
0.5 /10
15
1 /5
1 /5
29
Table 3. In Vitro Profile of Compound 29
33
6.2
18
9.0
4.0
4.5
AUCtotal (μM·h) iv/po
t1/2 (h) iv
1.2/3.9
5.0
1.3/8.7
7.1
2.3/3.2
14
1.3/0.029
11
Fpo (%)
33
34
28
b
4.5
a
Data are reported as averages over ≥3 animals. 80% PEG 400, 20%
c
water. 5% ethanol; 55% PEG 400; 20% propylene glycol, 20% TPGS.
d
e
70% PEG 400; 30% water. 90% PEG 400; 10% solutol.
met. stability CYP (t1/2 min) 32 (H), 11 (M), 20 (R), 7 (D), 3 (C)
met. stability UGT (t1/2 min) >120 (H, R, M, D, C)
PAMPA Papp (pH 7.4)
Caco Papp (a−b:b−a)
PXR-TA EC50 (μM)
human CYP IC50 (μM)
hERG IC50 (μM)
Na patch clamp
Ca2+ patch clamp IC50 (μM)
protein binding (% free)
1070 nm/s
122:56 nm/s
1.9 (22% Ymax)
2C9, 1.89; 2C8, 4.01; 2C19, 9.50; others, >10
17.4 (61% inh. at 30 μM)
<18% inh. at 10 μM (1 and 4 Hz)
0.76
to low clearance in mouse and rat, respectively, but higher
clearance in dog and particularly cyno, which also showed very
low oral bioavailability. High volumes of distribution were
observed across species. Additionally, liver accumulation was
seen in rats (24 h liver/plasma ratio = 8.3).
In vitro biotransformation studies in hepatocytes (H/R/D/C)
and in vivo metabolite identification studies in nu/nu mice from
the PK−PD study confirmed demethylation of the difluor-
omethylpyridine as the primary route of metabolism. The
demethylated metabolite of 29 was synthesized to confirm its
structure. While the metabolite was much less active against
IDO1 (IDO1 HWB IC50 > 1000 nM), it was still liable to
oxidative metabolism (CYP t1/2 = 24 (H), 36 (M), 26 (R), 38
+
H 0.8, M 1
correlated with improved in vitro oxidative metabolism in most
species (CYP t1/2 for 2 = 14 (H), 4 (M), 10 (R), 10 (D), 2 (C))
and lower protein binding (0.8/1% free for H/M for 29 vs <0.1%
free for both H/M for 1 vs <0.3/<0.2% free for H/M for 2).
Compound 29 had good intrinsic permeability and only modest
PXR activation. Like compound 2, 29 did show CYP inhibition
in some isoforms, but it was less potent (human CYP IC (μM)
(D), 7 (C)). The −OCD analogue of 29 was synthesized in an
3
attempt to attenuate the demethylation, but the in vitro oxidative
metabolic stability was not substantially improved (CYP t1/2
=
5
0
for 2: 0.74 for 2C9; 1.39 for 2C8; 3.37 for 2C19). Compound 29
showed some hERG inhibition at higher concentrations as well
as sodium and calcium channel inhibition, but the hERG
inhibition was still attenuated compared with 2 (87% inhibition
at 10 μM).
In a PK−PD study in a nu/nu mouse xenograft model
implanted with human SKOV3 cells (ovarian cancer cell line),
compound 29 had lower tumor exposures than 1 at doses of 60,
15 (H), 11 (M), 18 (R), 29 (D), 8 (C)).
In summary, structure-based drug design, torsional angle
energy minima, and the potential for conformational isomer-
ization of cyclohexane were considered in designing replace-
ments for the quinolines found in linrodostat (1) and BMS-
986242 (2). A stereodivergent synthesis was pursued that
identified a variety of successful quinoline replacements with
both cis and trans stereochemistry around the cyclohexane.
Strategic incorporation of fluorine and polarity into 2,3-
disubstituted 4-pyridyl analogues led to the identification of
compound 29. Despite lower exposures, compound 29 achieved
similar or even superior (180 mg/kg dose) kynurenine
1
20, and 180 mg/kg, and the exposures were not dose-
proportional for doses from 20 to 180 mg/kg (Table 4). Despite
the lower exposure, the 20 mg/kg dose of 29 still caused a
significant reduction in tumor kynurenine (58%), possibly due
1
147
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ACS Medicinal Chemistry Letters
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Letter
reduction in tumors in a human SKOV3 xenograft tumor mouse
model compared with 1.
Lorell N. Discenza − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Asoka Ranasinghe − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
ASSOCIATED CONTENT
■
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00236.
Mary F. Grubb − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Sarah C. Traeger − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Biological assay protocols, in vivo pharmacokinetic−
pharmacodynamic study protocols, experimental proce-
dures, and analytical data for all final compounds (PDF)
Xin Li − Bristol Myers Squibb, Research and Development,
Lawrence Township, New Jersey 08648, United States
Kathy A. Johnston − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Lisa Kopcho − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Mark Fereshteh − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Kimberly A. Foster − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Kevin Stefanski − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Diane Delpy − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Gopal Dhar − Department of Discovery Synthesis, Biocon
Bristol Myers Squibb R&D Centre, Syngene International Ltd.,
Bangalore 560099, India
Aravind Anandam − Department of Discovery Synthesis, Biocon
Bristol Myers Squibb R&D Centre, Syngene International Ltd.,
Bangalore 560099, India
Sandeep Mahankali − Department of Discovery Synthesis,
Biocon Bristol Myers Squibb R&D Centre, Syngene
International Ltd., Bangalore 560099, India
Shweta Padmanabhan − Department of Discovery Synthesis,
Biocon Bristol Myers Squibb R&D Centre, Syngene
International Ltd., Bangalore 560099, India
Prabhakar Rajanna − Department of Discovery Synthesis,
Biocon Bristol Myers Squibb R&D Centre, Syngene
International Ltd., Bangalore 560099, India
Venkata Murali − Department of Discovery Synthesis, Biocon
Bristol Myers Squibb R&D Centre, Syngene International Ltd.,
Bangalore 560099, India
T. Thanga Mariappan − Department of Discovery Synthesis,
Biocon Bristol Myers Squibb R&D Centre, Syngene
International Ltd., Bangalore 560099, India
Shabeerali Pattasseri − Department of Discovery Synthesis,
Biocon Bristol Myers Squibb R&D Centre, Syngene
International Ltd., Bangalore 560099, India
Roshan Y. Nimje − Department of Discovery Synthesis, Biocon
Bristol Myers Squibb R&D Centre, Syngene International Ltd.,
Bangalore 560099, India
AUTHOR INFORMATION
■
Corresponding Author
Emily C. Cherney − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States; orcid.org/0000-0003-1977-2900; Phone: 609-
2
52-6064; Email: emily.cherney@bms.com
Authors
Liping Zhang − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States; orcid.org/0000-0002-1797-7227
Weiwei Guo − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Audris Huang − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
David Williams − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Steven Seitz − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Weifang Shan − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Xiao Zhu − Bristol Myers Squibb, Research and Development,
Lawrence Township, New Jersey 08648, United States;
orcid.org/0000-0001-7647-4390
Johnni Gullo-Brown − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Derrick Maley − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Tai-an Lin − Bristol Myers Squibb, Research and Development,
Lawrence Township, New Jersey 08648, United States
John T. Hunt − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Christine Huang − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Zheng Yang − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Celia J. D’Arienzo − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Zhenqiu Hong − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
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pubs.acs.org/acsmedchemlett
Letter
James Kempson − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States; orcid.org/0000-0002-9540-3886
Richard Rampulla − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Arvind Mathur − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Anuradha Gupta − Department of Discovery Synthesis, Biocon
Bristol Myers Squibb R&D Centre, Syngene International Ltd.,
Bangalore 560099, India; orcid.org/0000-0002-4211-
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Robert Borzilleri − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Gregory Vite − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
Aaron Balog − Bristol Myers Squibb, Research and
Development, Lawrence Township, New Jersey 08648, United
States
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Complete contact information is available at:
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regulator of innate and adaptive immunity. Immunology Reviews 2012,
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Notes
The authors declare no competing financial interest.
(
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ABBREVIATIONS
D. R.; Vacca, C.; Orabona, C.; Bianchi, R.; Belladonna, M. L.; Volpi, C.;
Santamaria, P.; Fioretti, M. C.; Puccetti, P. The combined effects of
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■
TEA, triethylamine; THF, tetrahydrofuran; DPPA, diphenyl-
phosphoryl azide; DMPU, 1,3-dimethyl-3,4,5,6-tetrahydro-
(1H)-pyrimidinone; LDA, lithium diisopropylamide; MTBE,
methyl tert-butyl ether; B Pin , bis(pinocolato)diboron; EDCI,
-ethyl-3-(3-(dimethylamino)propyl)carbodiimide; HOBT, hy-
droxybenzotriazole; DIPEA, N,N-diisopropylethylamine;
HATU, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo-
4,5-b]pyridinium 3-oxide hexafluorophosphate; DMF, N,N-
dimethylformamide; EtI, ethyl iodide; MOMCl, methoxymethyl
chloride; NaOMe, sodium methoxide; H, human; M, mouse; R,
rat; D, dog; C, cyno
2
2
2
(16) Liu, H.; Huang, L.; Bradley, J.; Liu, K.; Bardhan, K.; Ron, D.;
Mellor, A. L.; Munn, D. H.; McGaha, T. L. GCN2-dependent metabolic
stress is essential for endotoxemic cytokine induction and pathology.
Mol. Cell. Biol. 2014, 34, 428−438.
1
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[
H.; Vahanian, N. N.; Link, C. J.; Prendergast, G. C. IDO inhibits a
tryptophan sufficiency signal that stimulates mTOR: a novel IDO
effector pathway targeted by D-1-methyl-tryptophan. Oncoimmunology
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5
(
1
enantioselective synthesis of compound 29 was developed and will be
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