Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms

Article abstract of DOI:10.1021/acsmedchemlett.5b00226

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C

Full text of DOI:10.1021/acsmedchemlett.5b00226

Letter
pubs.acs.org/acsmedchemlett
Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the
Treatment of Myeloproliferative Neoplasms
Honghe Wan, Gretchen M. Schroeder, Amy C. Hart, Jennifer Inghrim,† James Grebinski,‡
John S. Tokarski, Matthew V. Lorenzi,§ Dan You, Theresa Mcdevitt,§ Becky Penhallow, Ragini Vuppugalla,
Yueping Zhang, Xiaomei Gu, Ramaswamy Iyer, Louis J. Lombardo, George L. Trainor,∥ Stefan Ruepp,
Jonathan Lippy, Yuval Blat,⊥ John S. Sack, Javed A. Khan, Kevin Stefanski, Bogdan Sleczka, Arvind Mathur,
Jung-Hui Sun, Michael K. Wong, Dauh-Rurng Wu, Peng Li, Anuradha Gupta,# P. N. Arunachalam,#
Bala Pragalathan,# Sankara Narayanan,# Nanjundaswamy K.C.,# Prakasam Kuppusamy,#
and Ashok V. Purandare*
Bristol-Myers Squibb R&D, US Route 206 and Province Line Road, Princeton, New Jersey 08543-4000, United States
S
* Supporting Information
ABSTRACT: JAK2 kinase inhibitors are a promising new class of agents for the
treatment of myeloproliferative neoplasms and have potential for the treatment of other
diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME
guided refinement of C-4 heterocycles to address metabolic liability present in
dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with
excellent kinome selectivity, in vivo PD activity, and safety profile.
KEYWORDS: JAK2, selective inhibitor, myeloproliferative neoplasm, structure-guided design, BMS-911543
yeloproliferative neoplasms (MPNs) are a subset of
myeloid malignancies that are characterized by the
transgenic phenotype.6 Moreover, clinical testing of two small
molecule JAK2 inhibitors (e.g., ruxolitinib, fedratinib, pacriti-
nib) showed effects on splenomegaly and normalization of
blood counts (Figure 1).7−9 Based upon the late stage clinical
efficacy and tolerability profile, ruxolitinib was approved to treat
myelofibrosis (MF). Several other JAK2 inhibitors with varying
degrees of JAK family as well as overall kinome selectivity
profiles are in mid to late-stage clinical trials for MF.10
However, it is important to note that most of these compounds
also inhibit other JAK family members that could be associated
with immunosuppression, an undesired side effect for this
indication. Additionally, other off-target kinome activities (e.g.,
FLT3) could further compromise the anticipated high safety
window needed for long-term treatment in MPNs.
We have recently disclosed the identification of a potent and
highly selective JAK2 inhibitor 1.11 X-ray crystallographic
studies of 1 bound to the JAK2 kinase domain indicated that it
engages the Tyr931 residue through hydrogen bonding with
the thiazole nitrogen atom. In addition, unfavorable interactions
of the 4,5-dimethylthiazole fragment with nonconserved
residues in the extended hinge region of other JAK family
members provided high selectivity. Further ADME profiling
indicated that 1 was rapidly metabolized across species and was
M
expansion of a hematopoietic progenitor stem cell. MPNs
encompass polycythemia vera (PV), essential thrombocytope-
nia (ET), and primary myelofibrosis (PMF).1 In the majority of
cases, this cluster of diseases has been shown to be associated
with the somatic mutation JAK2-V617F that constitutively
activates the Janus kinase 2 (JAK2) enzyme, a member of the
JAK family of nonreceptor tyrosine kinases.2 In MPNs the
acquisition of the JAK2-V617F and other JAK2-STAT pathway
mutations result in cytokine-independent activation of the
pathway and the uncontrolled growth of hematopoietic cells
with erythrocytes, platelets, and granulocyte/monocytes being
the predominant lineages expanded in ET, PV, and PMF,
respectively.3 The uncontrolled growth of these cell lineages in
MPNs results in severe patient complications including
splenomegaly, hemorrhage, thrombosis, bone marrow fibrosis,
and transformation to acute myeloid leukemia. The overall
survival rate for patients afflicted with advanced myelofibrosis is
estimated to be 3−5 years.4
The causal role of JAK2 in MPNs is supported by significant
genetic and pharmacological data. Transgenic reconstitution of
JAK2 mutations into rodent bone marrow stem cells results in a
phenotype mirroring the main features of human MPNs
including splenomegaly, bone marrow fibrosis, and elevated
levels of certain hematopoietic lineages (e.g., erythrocytes,
leukocytes).5 Administration of small molecule JAK2 kinase
inhibitors reverses the pathophysiological features of the
Received: June 9, 2015
Accepted: July 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00226
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a
Scheme 1
a
Reagents and conditions: (a) benzoylisothiocyanate, acetone; then 1
N NaOH, ethanol, 60 °C, 72%; (b) 3-bromopentan-2-one, 60 °C,
44%; (c) methyl 2-bromo-3-oxobutanoate, ethanol, 65 °C, 84%; (d) 1
N NaOH, methanol, 65 °C, 93%; (e) methylamine, HATU, 2,6-
lutidine, DMF, 75%; (f) methyl 3-bromo-2-oxobutanoate, ethanol, 65
°C, 70%; (g) 1-bromo-1-(methylsulfonyl)propan-2-one ethanol, 65
°C, 62%; (h), 1,1-dioxo-1-thiomorpholine, HATU, 2,6-lutidine, DMF,
62%.
Figure 1. JAK2 inhibitors.
Table 1. Biotransformation and Thiazole Substitution
SAR
a b c
, ,
susceptible to generation of reactive metabolites (vide infra),
which prevented its further progression. Herein we report
ADMET and structure-guided optimization of heterocycles at
the C-4 position of the imidazopyrrolopyridine core leading to
the discovery of a highly selective JAK2 inhibitor, BMS-911543
(11), as a clinical candidate for the treatment of MPNs. Earlier
we have reported biological characterization of BMS-911543.12
In vitro biotransformation studies with compound 1 using
human liver microsomes revealed the formation of a thiourea
metabolite in significant amounts (15%). This metabolic
process presumably involves cytochrome P450-mediated
oxidation of the thiazole ring to an epoxide and subsequent
opening to form a diol intermediate. Decomposition of the diol
intermediate leads directly to a thiourea and diketo species
(Figure 2). Thioureas have the potential to form an active
metabolite in vivo, which could disrupt thyroid function and
could also have adverse effects in lung, liver, and bone
marrow.13
a
b
Assay protocols are provided in the Supporting Information. Assay
c
results are the average of at least two replicates. Percent thiourea
determined in human liver microsomes. Only trace levels detected by
mass spectrometry. No data was generated.
d
e
ing groups led to identification of potent JAK2 inhibitors
(compounds 5−7) , which were significantly less susceptible to
generation of the thiourea metabolite. However, such
substitutions caused considerable erosion of selectivity versus
other JAK family kinases. With respect to the selectivity of the
amide-containing thiazoles, differences in the JAK family
members around JAK2 Gln 853 may provide a rationale for
the loss in selectivity observed. The smaller serine present in
JAK3 would likely be able to accommodate the larger polar
amide-containing analogues. However, the arginine present in
JAK1 could be positioned such that a favorable hydrogen bond
to the amide at the 4- or 5-position on the thiazole may also
contribute to loss of selectivity (Figure 3 for JAK1 model with
compound 6). Further steric bulk on the amide (8) failed to
Figure 2. Metabolism of 1.
Literature reports indicated that the introduction of either
electron withdrawing groups on the thiazole or increasing
sterics may reduce initial complexation with CYP enzymes,
which could suppress oxidative ring opening.13,14 Accordingly,
analogues 4−8 were prepared using the approach outlined in
Scheme 1, starting from aminopyridine 2.15,16
As anticipated, adding substitution on the 4-methyl group
(4) maintained the JAK family selectivity profile of the parent
compound (Table 1). However, this change still resulted in
formation of thiourea in significant amounts in in vitro
biotransformation studies. Introduction of electron withdraw-
B
DOI: 10.1021/acsmedchemlett.5b00226
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ACS Medicinal Chemistry Letters
Letter
a
improve JAK family selectivity (compared to 1) and reduced
Scheme 2.
cellular potency.
a
Reagents and conditions: (a) acetyl isocyanate, acetone, 35 °C, 44%;
(b) methyl hydrazine, AcOH, 80 °C, 31%.
the triazole ring re-established the planarity (vide infra) and led
to the discovery of 1,5-dimethyl pyrazole analogue 11.
Compound 11, henceforth referred to as BMS-911543,
displayed an IC50 of 1.1 nM against JAK2 and was
approximately 350-, 75-, and 65-fold selective vs JAK1, JAK3,
and TYK2, respectively. Assessment of dissociation constants of
BMS-911543 for JAK1, JAK2, and JAK3 indicated greater
selectivity with Ki values of 110, 0.48, and 360 nM, respectively.
BMS-911543 was also evaluated in the KinomeScan (formerly
Ambit) panel (consisting of 451 kinases) as well as the internal
kinase panel to assess overall kinome selectivity. It displayed a
high level of selectivity across the kinome (see Supporting
Information for complete data set).18
The X-ray structure of BMS-911543 bound to the JAK2
kinase domain displayed a similar binding mode as 1. One of
the nitrogens of the pyrazole ring formed a hydrogen bond with
Tyr931 while maintaining coplanarity with the pyrrolopyridine
scaffold. The 1,5-dimethyl pyrazole occupied the extended
hinge region where key residue differences such as JAK2-
Gln853, JAK3-Ser826, JAK1-Arg868, and TYK2-Arg901
resulted in high selectivity within the JAK family (see Figure
4 for location of other nonconserved residues that may affect
selectivity).19
Figure 3. Model of 6 bound to the kinase catalytic domain of JAK1.
The carbons of 6 are colored in pink, and the carbons for JAK1 are
colored in green except for the residues near the C-4 group, which
differ in the JAK family (carbons are colored cyan). Oxygen atoms are
colored red, nitrogens blue, and sulfurs yellow. Hydrogen bonds are
indicated with dashed lines.
We next turned our attention to explore other closely related
five-membered isosteric dialkylthiazole ring isosteres that would
dispose alkyl groups in the extended hinge region similar to 1
(Table 2). Accordingly, triazole analogue 10 was prepared
(Scheme 2).17
Triazole 10 displayed modest JAK2 potency and high JAK
family selectivity. We postulated the loss of potency may be due
to a disfavored interaction of the triazole ring nitrogen with the
pyridyl nitrogen forcing the rings to adopt a less planar
conformation than compound 1. Removal of a nitrogen from
As expected the introduction of bulkier substitution on the
pyrazole nitrogen resulted in further enhancement of selectivity
within the JAK family (>140-fold) as observed for the analogue
12 while retaining the positive attributes found in BMS-911543.
a b
,
Table 2. C-4 Heterocycle SAR
Figure 4. Crystal structure of BMS-911543 bound to the kinase
catalytic domain of JAK2. The carbons of BMS-911543 are colored in
pink and the carbons for JAK2 are colored in green except for the
residues near the C-4 group, which differ in the JAK family (carbons
are colored cyan). Oxygens are colored red, nitrogens blue, and sulfurs
yellow. Hydrogen bonds are indicated with dashed lines.
a
b
Assay protocols are provided in the Supporting Information. Assay
results are the average of at least two replicates.
C
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In contrast, 1,3-dimethylpyrazole substitution (13) was found
to be detrimental to JAK2 potency and selectivity, probably due
to lack of the hydrogen bonding interaction with Tyr931 and
suboptimal hydrophobic interaction with the extended hinge
region. Consistent with our model, removal of the methyl
group from the pyrazole nitrogen (14) led to significant loss of
JAK family selectivity.
Although compound 12 displayed superior JAK family
selectivity, it demonstrated higher potential for QT prolonga-
tion in the patch clamp hERG channel assay (75% and 20%
inhibition for 12 and BMS-911543 at 30 μM, respectively). In
addition, 12 also showed an inferior pharmacokinetic profile
compared to BMS-911543 and hence was not progressed
further for additional studies.
dependent cell lines (A549, MDA-MB-231, MiaPaCa-2) were
significantly less sensitive to the inhibitor treatment. The
excellent biochemical selectivity versus JAK1/3 translated to
good cellular and functional selectivity in an IL-2 mediated T-
cell proliferation assay (IC50 990 nM).12 Also, cell lines that rely
on other JAK family members, including CTLL2 and parental
BaF3 cells stimulated with IL-3, showed weak antiproliferative
activity for BMS-911543 (IC50 2.9 and 3.5 μM, respectively)
(Figure 5).12
BMS-911543 and related pyrazoles were synthesized using
the reaction sequence depicted in Scheme 3. Condensation of 2
a
Scheme 3
Figure 5. Biochemical and cellular data summary of BMS-911543.
BMS-911543 suppressed the pSTAT5 levels (mediated by
wild type JAK2) relative to vehicle control when stimulated
with thrombopoetin (TPO) in a mouse pharmacodynamic
model.12 The responses were dose dependent and resulted in
nearly complete normalization of pSTAT5 levels for 18 h at the
highest oral dose of 30 mg/kg. At an intermediate 10 mg/kg
oral dose, ∼65% reduction was observed up to 18 h, whereas at
the 5 mg/kg dose, approximately 50% reduction in pSTAT5 for
8 h was achieved. Observed pSTAT5 reductions correlated with
exposures of BMS-911543, with AUC0−8h values of 23, 41, and
109 μM·h, respectively, for dose levels of 5, 10, and 30 mg/kg.
In addition, BMS-911543 demonstrated a potent and sustained
(2 mg/kg up to 7 h) PD effect in blocking pSTAT5 formation
in mice grafted with human SET-2 cells harboring JAK2-V617F
mutation.
In in vitro ADMET profiling assays, BMS-911543 showed
good metabolic stability, excellent intrinsic permeability, and
moderate drug−drug interaction potential based upon CYP
inhibition of the CYP3A4 and CYP1A2 isoforms. In an in vitro
safety panel consisting of 45 targets, BMS-911543 showed IC50
> 25 μM for all targets except PDE4 (IC50 5.6 μM). BMS-
911543 was not mutagenic or clastogenic in exploratory Ames
and in vitro micronucleus assays, respectively. In addition to
weak activity in the patch clamp hERG assay, BMS-911543 also
showed similar trends in in vitro Na+ and Ca2+ binding assays,
indicating a low potential to cause cardiovascular effects (Table
3). In in vitro biotransformation studies with human liver
microsomes, BMS-911543 formed small amounts (∼4%) of 1-
demethylated metabolite (compound 14) as the major
metabolite.
a
Reagents and conditions: (a) NaH, 4,4-bis(methylthio)but-3-en-2-
one, DMF, RT, 75%; (b) methyl hydrazine, EtOH, 85 °C, 30%; (c)
tert-butyl 1-methylhydrazinecarboxylate, AcOH, 50 °C; (d) formic
acid, 60 °C, 65%.
with 4,4-bis(methylthio)but-3-en-2-one gave intermediate 15.
Initially, 14 was directly combined with methyl hydrazine
furnishing a 1:9 mixture of desired 1,5- and undesired 1,3-
dimethylpyrazole regioisomers (BMS-911543 and 13, respec-
tively).20 By subjecting 15 to condensation with tert-butyl 1-
methylhydrazinecarboxylate followed by subsequent treatment
with formic acid, BMS-911543 was formed exclusively.21 The
reaction sequence proceeds through the kinetically formed
intermediate 16, which undergoes cyclization after Boc-
deprotection to yield the desired regioisomer. Pyrazoles 12
and 14 were prepared from 15 in analogous manner as BMS-
911543.
In cellular assays, BMS-911543 showed potent antiprolifer-
ative activity in the SET-2 as well as BaF3-V617F engineered
cell lines (both dependent upon JAK2 pathway), with IC50
values of 60 and 70 nM, respectively. The antiproliferative
activity of BMS-911543 in SET-2 and BaF3-V617F cells
correlated with similar activity on constitutively active pSTAT5
(IC50 80 and 65 nM, respectively). In contrast, non-JAK2-
The pharmacokinetics of BMS-911543 was investigated in
mice, rats, dogs, and monkeys (Table 4 and Supporting
Informatoin). The absolute oral bioavailability in solution was
D
DOI: 10.1021/acsmedchemlett.5b00226
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⊥ARMGO Pharma Inc., 777 Old Saw Mill River Road,
Tarrytown, New York 10591, United States.
Table 3. In Vitro ADMET Profile of BMS-911543
metabolic stability (T1/2
min)
49 (H), 108 (M), 69 (R), 70 (D)
#Biocon BMS R&D Center (BBRC), Bangalore, Syngene
International Ltd., Plot No. 2 and 3, Bommasandra IV Phase,
Jigani Link Road, Bangalore 560 099, India.
PAMPA (pH 7.4)
HLM CYP IC50
698 nm/sec
all >40 μM; except CYP3A4 (3 μM) and 1A2
(1 μM)
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
hERG patch clamp
Na+ patch clamp
Ca2+ patch clamp IC50
PXR EC50
20% inh at 30 μM
<10% inh at 10 μM (1 Hz and 4 Hz)
>80 μM
>50 μM
>50 μM
The authors declare no competing financial interest.
HEPG2 IC50
ACKNOWLEDGMENTS
■
Table 4. Pharmacokinetic Profile of BMS-911543
We thank Drug Discovery, Synthesis, Rulin Zhao and Bei Wang
for their help in preparation of BMS-911543. We also thank T.
G. Murali Dhar for his critical input during the preparation of
the manuscript.
a
b
c
d
PK
mouse
rat
dog
cyno
CL (mL/min/kg)
Vss (L/kg)
T1/2 (h)
0.55
0.26
5.1
0.7
0.3
5
6.5
1.6
2.2
82
5.3
1.1
2.4
53
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F (%)
100
100
■
a
b
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details for key compounds and biological
protocols. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acsmedchemlett.5b00226.
■
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AUTHOR INFORMATION
Corresponding Author
*Tel: +1-609-252-4320. E-mail: ashok.purandare@bms.com.
■
Present Addresses
†Immunomedics, 300 The American Road, Morris Plains, New
Jersey 07950, United States.
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Expert Opin. Invest. Drugs 2013, 22, 687−699.
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United States.
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§Janssen Pharmaceutical Companies of Johnson and Johnson,
1400 McKean Rdoa, Spring House, Pennsylvania 19002,
United States.
∥BioMotiv, 20600 Chagrin Boulevard, Suite 210, Cleveland,
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DOI: 10.1021/acsmedchemlett.5b00226
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX