Development of a Scalable Method for Manufacturing the Central Core of CD73 Inhibitor AB680

Article abstract of DOI:10.1021/acs.oprd.0c00469

AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the manufacturing of the azaindazole central core. This synthesis features an N-oxide formation followed by an α-chlorination with POCl3 leading to the formation of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 1 in high yield and 99.5% UV purity. This method was successfully performed on multikilogram scale to support the synthesis of AB680.

Full text of DOI:10.1021/acs.oprd.0c00469

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Development of a Scalable Method for Manufacturing the Central
Core of CD73 Inhibitor AB680
Jeremy Fournier,* Xuelei Yan, Anh T. Tran, Rebecca L. Grange, Steven D. Jacob, Jaroslaw Kalisiak,
Kenneth V. Lawson, Eric F. Connor, Manmohan R. Leleti, and Jay P. Powers
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ABSTRACT: AB680 is a highly potent CD73 small molecule inhibitor discovered and developed by Arcus Biosciences, currently in
clinical trials for the treatment of pancreatic cancer. Here, we report the development of a scalable and practical method for the
manufacturing of the azaindazole central core. This synthesis features an N-oxide formation followed by an α-chlorination with
POCl3 leading to the formation of 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 1 in high yield and 99.5% UV purity. This method was
successfully performed on multikilogram scale to support the synthesis of AB680.
KEYWORDS: AB680, CD73, chlorination, azaindazole
amino-pyrrazole 3 by reacting [(4-methoxyphenyl)methyl]-
hydrazine and ethyl (ethoxymethylene)cyanoacetate in 63%
yield.8 Next, pyrrazole 3 was subjected to a condensation
reaction to form β-keto ester 4, which was then decarboxylated
under basic conditions to provide pyrazolopyridine 5 in 87%
yield over two steps. Compound 5 was then chlorinated in the
presence of phenylphosphonic dichloride9 at 170 °C followed
by PMB deprotection in neat TFA to afford 4,6-dichloro-1H-
pyrazolo[3,4-b]pyridine 1. We were also able to develop a one-
pot construction of the pyrazolo-pyridine heterocycle by
reacting amino-pyrazole 7 and Meldrum’s acid in the presence
of POCl3 and BnEt3N+Cl−, allowing us to isolate the PMB-
protected dichloro heterocycle 6 in 25% yield (Scheme 1B).10
Although these synthetic approaches have been shown to be
robust enough to provide multigrams of material to support
SAR studies and the discovery of AB680, several problems
associated with these synthetic sequences emerged during the
development of a process friendly route. First, the chlorination
reaction in the first route was carried out at very high
temperature (170 °C) and yields were not always consistent.
Second the TFA mediated PMB deprotection generated a large
amount of a polymer which was not easily removable without
the use of column chromatography.
INTRODUCTION
■
A high concentration of adenosine in the tumor microenviron-
ment, caused by high cellular turnover, immunogenic cell
death due to chemotherapy, and a variety of nonlytic
mechanisms, has been known to suppress immune response
via inhibition of immune cell activation. In fact, cell death
generates extracellular adenosine triphosphate (ATP) which is
converted to adenosine monophosphate (AMP) by ecto-
nucleoside CD39, and then to adenosine by ecto-5′-
nucleotidase CD73.1−4 The adenosine produced in the
tumor microenvironment suppresses the immune response of
T cells, NK cells, dendritic cells, and macrophages through
activation of A2aR and A2bR receptors.5 As CD73 has been
found to be overexpressed in different tumor types,6 we
developed an exceptionally potent small molecule inhibitor
(AB680, Ki = 5 pM),7 currently in clinical trials in cancer
patients (Figure 1). In order to support ongoing clinical trials,
In order to overcome these challenges, we developed a
second generation synthesis of heterocycle 1 which we
believed would be more process friendly and would allow us
to provide kilograms of material to support the ongoing clinical
trials. The initial plan was to start with readily available 7-
azaindole (Scheme 2) and perform two N-oxidation/
Figure 1. Structure of CD73 inhibitor AB680.
we developed a manufacturing process and this contribution
describes the challenges we encountered in the large scale
synthesis of the azaindazole central core.
Received: October 19, 2020
RESULTS AND DISCUSSION
Our first generation synthesis (Scheme 1A) of 4,6-dichloro-
1H-pyrazolo[3,4-b]pyridine 1 started with the formation of
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© XXXX American Chemical Society
A

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Scheme 1. First Generation Synthesis of 4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine 1
Scheme 2. Double Oxidation/Chlorination Sequence
chlorination sequences to access 4,6-dichloro-1H-pyrazolo[3,4-
b]pyridine 1 in four steps.11 When performed on small scale,
the two N-oxidation/chlorination sequences produced drasti-
cally different yields. Indeed, the oxidation of 7-azaindazole in
the presence of mCPBA resulted in clean formation of the
corresponding N-oxide which was further chlorinated with
POCl3 to provide a mixture of 4-chloro- and 6-chloro-
azaindazole (10 and 11) in a 2:1 ratio and 90% overall yield.
This mixture of compounds was resubjected to the same set of
conditions which allowed us to isolate the desired 4,6-dichloro-
1H-pyrazolo[3,4-b]pyridine 1 but in only 37% yield.
In order to identify the cause of the low yield observed, we
carried out the N-oxidation/chlorination sequence on both
monochloro azaindazoles separately. First, we focused our
efforts on 6-chloroazaindazole derivative 11, and we observed
that the use of mCPBA oxidation conditions did not give
satisfactory yields of the N-oxide product (Table 1, entry 1).
Following this observation, we investigated other conditions
that would allow us to get the N-oxide intermediate 12 in
acceptable yield. First, changing the oxidant to H2O2 in water/
acetic acid did not result in any conversion either (Table 1,
entry 2). Interestingly, the use of urea·H2O2 in acetonitrile
showed promise, as N-oxide 12 was formed in 70% conversion
(Table 1, entry 3).12 We then screened additional solvents to
try to improve the conversion and found MTBE and DME to
be the best solvents, affording >88% conversion (Table 1,
entries 7−8). Although the conversion was excellent, the
isolation of N-oxide 12 turned out to be challenging, which
resulted in low overall yield. To overcome this issue, we tried
Table 1. Optimization of 6-Cl-Azaindazole Oxidation
Entry
Oxidant
mCPBA
H2O2
Urea·H2O2, TFAA
Urea·H2O2, TFAA
Urea·H2O2, TFAA
Urea·H2O2, TFAA
Urea·H2O2, TFAA
Urea·H2O2, TFAA
Conditions
Conversion
1
2
3
4
5
6
7
8
AcOH, 80 °C
H2O, AcOH, 95 °C
CH3CN, rt
dioxane, rt
THF, rt
methanol, rt
MTBE, rt
<5%
<5%
70%
26%
21%
<5%
88%
90%
DME, rt
to optimize a one-pot N-oxidation followed by chlorination,
but to our disappointment this was unsuccessful.
On the other hand, when 4-chloro-azaindazole 10 was used
as starting material, the oxidation/chlorination sequence
proved to be very efficient, providing the desired dichloro-
azaindazole 1 in 87% overall yield (Scheme 3).
Based on these results, we tried to optimize the first N-
oxidation/chlorination sequence to favor the formation of 4-
chloro-azaindazole 10 over 6-chloro-azaindazole 11 (see Table
2). The use of an alternate chlorine source like PCl3, MsCl, or
oxalyl chloride resulted in complex reaction mixtures (Table 2,
entries 2−4), and varying the solvent did not allow us to obtain
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Scheme 3. Oxidation/Chlorination from Mono-chloro-azaindazoles
Table 2. Optimization of Oxidation/Chlorination Sequence
Entry
Chlorinating agent
Conditions
10:11 ratio
1.2:1
complex mixture
complex mixture
complex mixture
1.5:1
1:1.5
2:1
1
2
3
4
5
6
7
8
POCl3
PCl3
MsCl
Oxalyl chloride
POCl3
POCl3
POCl3
POCl3
CH3CN, rt
CH3CN, rt
CH3CN, 50 °C
CH3CN, 50 °C
CH2Cl2, rt
Toluene, rt
DMF, rt
NMP, rt
1:1
Scheme 4. Impurity Profile of 4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine 1
Scheme 5. Scale-up Synthesis of 4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine 1
sufficient selectivity to pursue this route from 7-azaindazole 9
(Table 2, entries 5−8).
chlorine source helped us eliminate the formation of dimer 14
and access 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 1 in high
purity. As a result, we decided to use 2 equiv of POCl3 and 0.5
equiv of Bn(Et)3N+Cl− as our final conditions for the
chlorination step. This procedure was then transferred to a
CRO which carried out the reaction on up to 30 kg, isolating
the dichloroazaindazole 1 in 58% overall yield and 99.5%
purity, which allowed us to support the phase 1 clinical trial of
AB680 (Scheme 5).
However, as 4-chloroazaindazole 10 was commercially
available and has shown high yields we decided to optimize
that two-step sequence. There were mainly two issues that
needed to be fixed to obtain high purity material (>99%)
required for scale-up synthesis, as the final compound was
contaminated with 5% of residual unreacted starting material
and 5% of dimer 14, the formation of which can be explained
by the high concentration used in the reaction (Scheme 4).
First, the difference in pKa between monocholoro-
azaindazole 10 and dichloro-azaindazole 1 allowed us to
remove unreacted starting material by filtration under acidic
conditions. Concerning the elimination of the second impurity,
we first tried to decrease the concentration of the reaction to
avoid the formation of the dimer, or increase the amount of
chlorinating agent, but the results were not conclusive.
However, the use of a tetraalkylammonium salt as an additional
CONCLUSION
■
In summary, we successfully developed a practical and scalable
method for the synthesis of 4,6-dichloro-1H-pyrazolo[3,4-
b]pyridine 1, to support the scale-up synthesis of AB680. The
method features an N-oxidation/chlorination two-step se-
quence that allowed us to access 4,6-dichloro-1H-pyrazolo[3,4-
b]pyridine 1 in high yield and 99.5% UV purity, on up to 30
kg, without the use of column chromatography.
C
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188.1. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.53 (s,
1H).
EXPERIMENTAL SECTION
■
Ethyl 5-Amino-1-[(4-methoxyphenyl)methyl]-
pyrazole-4-carboxylate (3). Ethyl (ethoxymethylene)cyano-
acetate (50.5 g, 299.0 mmol, 1 equiv) was dissolved in
anhydrous EtOH (350 mL), and then (4-methoxyphenyl)-
methylhydrazine (50 g, 328.9 mmol, 1.1 equiv) was added.
The reaction mixture was stirred under reflux overnight and
then evaporated. The solid residue was washed with MTBE to
give a white solid (55.5 g, 63%). ESI MS [M + H]+ for
4,6-Dichloro-1-[(4-methoxyphenyl)methyl]pyrazolo-
[3,4-b]pyridine (6). To a mixture of 2-[(4-methoxyphenyl)-
methyl]pyrazol-3-amine 7 (20 g, 98 mmol, 1 equiv) and
Meldrum’s acid 8 (14 g, 98 mmol, 1.0 equiv) in POCl3 (91
mL, 980 mmol, 10 equiv) was added benzyltriethylammonium
chloride (45 g, 196 mmol, 2 equiv), and the reaction mixture
was heated to 110 °C for 16 h. At this point, the reaction
mixture was cooled to rt and poured over crushed ice. The pH
of the solution was carefully adjusted to 10 using 10 N NaOH
solution and extracted into CHCl3 (3 × 200 mL). Layers were
separated, and combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Solvent was removed
in vacuo to give a crude residue that was purified by column
chromatography (SiO2, gradient 0% to 35% EtOAc in hexanes)
to give intermediate 6 (7.55 g, 25%).
4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine (1). To a
mixture of 1H-Pyrazolo[3,4-b]pyridine 9 (4.75 g, 39.9 mmol,
1 equiv) in NMP (30 mL) was added m-CPBA (11.0 g, 47.9
mmol, 1.2 equiv) portionwise over 5 min. The reaction was
stirred at rt for 1 h. Upon completion of reaction, MTBE (100
mL) was added and the mixture was stirred for 30 min at 0 °C.
The reaction mixture was filtered, the filter cake was triturated
with MTBE, and the resulting solid was dried under vacuum.
The solid was dispersed in DMF (20 mL), and POCl3 (10 mL,
107.3 mmol, 2.7 equiv) was added dropwise at 0 °C. The
reaction was stirred at rt for 30 min. The reaction was then
quenched with 20% NaOHaq until pH = 9 at 0 °C. The
reaction mixture was diluted with water (20 mL) and filtered,
and the filter cake was dried under vacuum to give a mixture of
4-chloro-1H-pyrazolo[3,4-b]pyridine 10 and 6-chloro-1H-
pyrazolo[3,4-b]pyridine 11 (5.55 g, 90%) in a 2:1 ratio.
The previous mixture was dissolved in NMP (27 mL) and
m-CPBA (10.8 g, 47.0 mmol, 1.3 equiv) portionwise over 5
min. The reaction was stirred at rt for 1 h, MTBE (100 mL)
was added, and the mixture was stirred for 30 min at 0 °C. The
reaction mixture was filtered, the filter cake was triturated with
MTBE, and the solid was dried under vacuum. The resulting
N-oxide intermediate (2.84 g, 16.7 mmol) was dispersed in
CH3CN (14 mL), and POCl3 (6.2 mL, 67 mmol, 4 equiv) was
added dropwise at 0 °C. The reaction was stirred at rt for 30
min. The reaction was then quenched with 20% NaOHaq until
pH = 9 at 0 °C. The reaction mixture was diluted with water
(20 mL) and filtered, and the filter cake was dried under
vacuum to give 4,6-dichloro-1H-pyrazolo[3,4-b]pyridine 1
(2.49 g, 37%).
1
C14H18N3O3, calcd 276.1, found 276.2. H NMR (400 MHz,
Chloroform-d) δ 7.66 (s, 1H), 7.17−7.08 (m, 2H), 6.92−6.83
(m, 2H), 5.09 (s, 2H), 4.83 (s, 2H), 4.25 (qd, J = 2.1, 7.1 Hz,
2H), 3.79 (s, 3H), 1.32 (td, J = 2.2, 7.1 Hz, 3H).
Ethyl 1-[(4-Methoxyphenyl)methyl]-4,6-dioxo-7H-
pyrazolo[3,4-b]pyridine-5-carboxylate (4). Diethyl malo-
nate (90 mL, 0.59 mol, 4 equiv) was dissolved in anhydrous
EtOH (300 mL) and cooled to 0 °C (ice bath). A 21%
solution of NaOEt in EtOH (220 mL, 0.59 mol, 4 equiv) was
added dropwise (within 10 min), followed by the removal of
the cooling bath, and the reaction was stirred at room
temperature for 15 min. Ethyl 5-amino-1-[(4-methoxyphenyl)-
methyl]pyrazole-4-carboxylate 3 (40.4 g, 147 mmol, 1 equiv)
was added in portions (within 2 min), and the reaction mixture
was stirred under reflux for 5 days and then evaporated. The
residue was diluted with H2O (1.2 L) and neutralized to pH ≈
5 using AcOH. The product was filtered off, washed with H2O
(200 mL), dried under vacuum, and used without further
purification.
1-[(4-Methoxyphenyl)methyl]pyrazolo[3,4-b]-
pyridine-4,6-diol (5). Ethyl 1-[(4-methoxyphenyl)methyl]-
4,6-dioxo-7H-pyrazolo[3,4-b]pyridine-5-carboxylate 4 (48.4 g,
141.1 mmol, 1 equiv) was dissolved in 15% aqueous NaOH
(500 mL) and stirred under reflux for 5 h. The mixture was
cooled to 0 °C and carefully neutralized with AcOH until pH
≈ 5. White solid was filtered off, washed with H2O (100 mL),
and dried under vacuum (38 g, 87% over 2 steps). ESI MS [M
+ H]+ for C14H14N3O3, calcd 272.1, found 272.2. H NMR
1
(400 MHz, DMSO-d6) δ 7.1 (s, 1H), 7.18−7.09 (m, 2H),
6.88−6.80 (m, 2H), 5.26 (s, 2H), 5.09 (s, 1H), 3.68 (s, 3H).
4,6-Dichloro-1-[(4-methoxyphenyl)methyl]pyrazolo-
[3,4-b]pyridine (6). 1-[(4-Methoxyphenyl)methyl]pyrazolo-
[3,4-b]pyridine-4,6-diol 5 (38 g, 140.2 mmol, 1 equiv) and
phenylphosphonic dichloride (79.5 mL, 560.8 mmol, 4 equiv)
were stirred at 170 °C for 7 h, then cooled to ∼80 °C, and
poured into vigorously stirred ice. Brown, sticky material
precipitated that upon extensive stirring turned into a solid.
The ice cold mixture was neutralized with concentrated
aqueous NH3 until pH ≈ 7, and the product was extracted
using CH2Cl2 (2 × 400 mL). Combined organics were dried
over MgSO4, filtered, and evaporated to give product that was
used without further purification (24 g, 55%). ESI MS [M +
General Procedure for the Oxidation of 6-Chloro-1H-
pyrazolo[3,4-b]pyridine (11). To a solution of trifluoro-
acetic anhydride (0.72 mL, 5.2 mmol, 4.0 equiv) in
dimethoxymethane (1.9 mL) was added urea hydrogen
peroxide (490 mg, 5.2 mmol, 4.0 equiv), and the reaction
mixture was stirred at room temperature for 15 min. At this
point, intermediate 11 (200 mg, 1.3 mmol, 1 equiv) was added
in one portion and the reaction mixture was stirred at room
temperature for an additional 2.5 h. The conversion was
measured by LCMS.
4-Chloro-1H-pyrazolo[3,4-b]pyridine 10 and 6-chloro-1H-
pyrazolo[3,4-b]pyridine (11). To a mixture of 1H-pyrazolo-
[3,4-b]pyridine 9 (4.95 g, 41.6 mmol, 1 equiv) in NMP (32
mL) was added m-CPBA (11.5 g, 49.8 mmol, 1.2 equiv)
portionwise over 5 min. The reaction was stirred at rt for 1 h.
Upon completion of reaction, MTBE (100 mL) was added and
H]+ for C14H12Cl2N3O, calcd 308.0, found 308.1. H NMR
1
(400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.58 (s, 1H), 7.22−7.17
(m, 2H), 6.88−6.83 (m, 2H), 5.54 (s, 2H), 3.68 (s, 3H).
4,6-Dichloro-1H-pyrazolo[3,4-b]pyridine (1). 4,6-Di-
chloro-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine
6 (22 g, 71.4 mmol, 1 equiv) was dissolved in TFA (75 mL)
and stirred at 60 °C for 12 h, then cooled down, and poured
into H2O (600 mL). A gray solid was filtered off, washed with
saturated NaHCO3 and then with H2O, and dried under
vacuum. ESI MS [M + H]+ for C6H4Cl2N3, calcd 188.0, found
D
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the mixture was stirred for 30 min at 0 °C. The reaction
mixture was filtered, the filter cake was triturated with MTBE,
and the resulting solid was dried under vacuum to provide N-
oxide 13 (5.10 g, 91%).
Steven D. Jacob − Arcus Biosciences, Inc., Hayward,
California 94545, United States
Jaroslaw Kalisiak − Arcus Biosciences, Inc., Hayward,
California 94545, United States
Kenneth V. Lawson − Arcus Biosciences, Inc., Hayward,
California 94545, United States; orcid.org/0000-0001-
5094-6337
Eric F. Connor − Arcus Biosciences, Inc., Hayward, California
94545, United States
Manmohan R. Leleti − Arcus Biosciences, Inc., Hayward,
California 94545, United States
Jay P. Powers − Arcus Biosciences, Inc., Hayward, California
94545, United States
N-Oxide 13 (200 mg, 1.48 mmol, 1 equiv) was dispersed in
solvent (1.5 mL), and the chlorinating reagent (5.92 mmol, 4
equiv) was added dropwise at 0 °C. The reaction mixture was
then stirred at rt or 50 °C until consumption of starting
material (see Table 2), quenched with 20% NaOHaq, and
extracted with EtOAc. The layers were separated, and the
combined organic layers were washed with brine, evaporated,
and dried over anhydrous Na2SO4. The ratio of 4-chloro-1H-
pyrazolo[3,4-b]pyridine 10 and 6-chloro-1H-pyrazolo[3,4-b]-
1
pyridine 11 was measured by H NMR of the crude mixture.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00469
Large Scale Synthesis of 4,6-Dichloro-1H-pyrazolo[3,4-
b]pyridine (1). To a 1000 L reactor was charged NMP (400.0
kg) and 4-chloro-1H-pyrazolo[3,4-b]pyridine 10 (30.0 kg,
195.4 mol, 1 equiv). m-CPBA (77.5 kg, 449.4 mol, 2.3 equiv)
was added portionwise below 20 °C. The reaction was stirred
at 20 °C for 20 h. Upon completion of reaction, MTBE (440.0
kg) was added and the mixture was stirred for 1 h. The
reaction mixture was filtered, the filter cake was triturated with
MTBE (150.0 kg), the resulting slurry was filtered, and the
filter cake was washed with MTBE (150.0 kg). The filter cake
was dried at 45−50 °C to give N-oxide 15 (30.0 kg, 90.0%
yield, 97.2 by HPLC) as a yellow solid. To a 500 L reactor
were charged CH3CN (265.0 kg), N-oxide 15 (28.0 kg, 165.1
mol, 1 equiv), and Bn(Et)3Cl (18.8 kg, 82.6 mol, 0.5 equiv).
POCl3 (51.3 kg, 330.2 mol, 2 equiv) was added below 20 °C.
The reaction was stirred at 10−20 °C for 2 h. Upon
completion of reaction, water (280.0 kg) was added below
20 °C and then stirred for 2 h. The reaction mixture was
filtered. The filter cake was triturated with sat. NaHCO3
solution (300.0 kg) and then diluted with water (280.0 kg),
the resulting slurry was filtered, and the filter cake was dried at
45−50 °C to give crude product (23.0 kg) which was dissolved
in EA (180.0 kg) at reflux and then filtered. The filtrate was
concentrated to approximately 80 L and heptane was added
(70.0 kg), the resulting mixture was cooled to 0−5 °C and
filtered, and the filtered cake was dried to offer 4,6-dichloro-
1H-pyrazolo[3,4-b]pyridine 1 (20.0 kg, 64.4% yield, 99.7% by
HPLC) as an off-white solid.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS USED
■
ADO, adenosine monophosphate; AMP, adenosine mono-
phosphate; ATP, adenosine triphosphate; CD73, cluster of
differentiation 73, ecto-5′-nucleotidase; CD39, cluster of
differentiation 39; DMF, N,N-dimethylformamide; DMSO,
dimethyl sulfoxide; NMP, N-methylpyrrolidone; pTsOH, para-
toluenesulfonic acid; T1/2, half-life; TFA, trifluoroacetic acid;
TFAA, trifluoroacetic anhydride; THF, tetrahydrofuran; PMB,
para-methoxybenzyl; SAR, structure−activity relationship;
EtOH, ethanol; mCPBA, meta-chloroperoxybenzoic acid;
DME, 1,2-dimethoxyethane; MTBE, methyl tert-butyl ether;
AcOH, acetic acid; MsCl, methanesulfonyl chloride; rt, room
temperature; EtOAc, ethyl acetate.
REFERENCES
■
́
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ASSOCIATED CONTENT
* Supporting Information
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■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00469.
1
General information, H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jeremy Fournier − Arcus Biosciences, Inc., Hayward,
California 94545, United States; orcid.org/0000-0003-
3162-3588; Email: jfournier@arcusbio.com
A. R.; Rockenbach, L.; Farias, P. F.; Wink, M. R.; Delgado-Canedo,
̃
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Authors
Xuelei Yan − Arcus Biosciences, Inc., Hayward, California
94545, United States
Anh T. Tran − Arcus Biosciences, Inc., Hayward, California
94545, United States
Rebecca L. Grange − Arcus Biosciences, Inc., Hayward,
California 94545, United States
E
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