MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors

Article abstract of DOI:10.1021/ml500409n

The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective,

Full text of DOI:10.1021/ml500409n

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Letter
pubs.acs.org/acsmedchemlett
MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral
Aurora A Inhibitors
Todd B. Sells,* Ryan Chau, Jeffrey A. Ecsedy, Rachel E. Gershman, Kara Hoar, Jessica Huck,
David A. Janowick, Vivek J. Kadambi, Patrick J. LeRoy, Matthew Stirling, Stephen G. Stroud, Tricia J. Vos,
Gabriel S. Weatherhead, Deborah R. Wysong, Mengkun Zhang, Suresh K. Balani, Joseph B. Bolen,
Mark G. Manfredi, and Christopher F. Claiborne
Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: The Aurora kinases are essential for cell mitosis, and the dysregulation of
Aurora A and B have been linked to the etiology of human cancers. Investigational
agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity,
selective, orally bioavailable inhibitors of Aurora A that have advanced into human
clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III
clinical trials in hematological malignancies and solid tumors.
KEYWORDS: Alisertib, Aurora A kinase, MLN8054, MLN8237
he Aurora kinases A and B are serine/threonine kinases
that are essential for normal progression through mitosis.
T
Aurora A and B overexpression occurs in both solid and
hematological malignancies. Loss of function or inhibition of
Aurora A or B results in aberrant mitosis that can lead to cell-
cycle arrest and apoptosis. These findings have inspired
numerous drug discovery efforts in search of clinically useful
inhibitors of the Aurora kinases for cancer therapy.1 While
other organizations have pursued the development of Aurora B
or pan-Aurora kinase inhibitors, we sought to identify a
selective Aurora A kinase inhibitor. We report here the
discovery of MLN8054 (8) and alisertib (MLN8237, 10),
selective Aurora A inhibitors that have advanced into human
clinic trials.2−4
Figure 1. Structure, logP, and Aurora A ligand efficiency (LE) of
BBL22, MLN8054, and alisertib.
One of our approaches toward identifying small molecule
inhibitors of Aurora A utilized a traditional high throughput
screen. Scaffolds that we identified have also been identified by
other groups and have been subsequently advanced into the
clinic as Aurora B selective or pan Aurora kinase inhibitors.5,6
In addition to our pursuing a traditional screening approach
was our investigation of the pyrimidobenzazepine BBL22 (1,
Figure 1), which was reported to induce G2/M cell cycle arrest
and apoptosis in human tumor cell lines.7 In an enzymatic
assay, 1 inhibited Aurora A kinase activity at micromolar
concentrations (Table 1).2,3 Human tumor cell lines treated
with 1 underwent cell cycle progression and mitotic defects
followed by cell death, phenotypes consistent with Aurora A
inhibition using RNA interference and antibody micro-
injection.3,8 Unlike the scaffolds identified in our high
throughput screen, the pyrimidobenzazepines, exemplified by
1, represented a unique starting point toward identifying an
Aurora kinase inhibitor that meets the requirements for clinical
investigation. We chose to investigate this scaffold for its
potential to provide a potent and selective, orally active
inhibitor of Aurora A kinase.
Our initial medicinal chemistry efforts were focused on
establishing whether suitable Aurora A potency could be
obtained with this scaffold. To enable analogue generation, we
developed routes that would allow for modification of each of
the aromatic rings and would also facilitate substitution on the
Received: October 6, 2014
Accepted: April 22, 2015
© XXXX American Chemical Society
A
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functionalized guanidines, producing the target pyrimidobenza-
zepines 7−10.
Table 1. Enzyme and Cellular Activity
AurA
(nM)
pT288
a
pHisH3
a
HCT116 BrdU
b
Encouraging progress optimizing the pyrimidobenzazepine
scaffold, as demonstrated through the favorable profile
observed with 7, provided the impetus for the synthesis of
numerous analogues within this series.9,11 Of particular note
from the resulting structure−activity relationship (SAR) was an
improvement in cellular potency that could be obtained with an
additional substituent in the ortho-position of the 7-phenyl
ring. Incorporation of a fluorine at this position provided
MLN8054 (8). In addition to an increased potency in cells,
MLN8054 is 150-fold selective for Aurora A over Aurora B in
HCT116 cells (Table 1). MLN8054 is a reversible, ATP
competitive inhibitor of recombinant Aurora A (Ki = 7 nM,
apparent Koff = 8 s−1). Additionally, MLN8054 displayed good
selectivity against a panel of known kinases.12 MLN8054 bound
to the kinase domain of Aurora A has been reported to result in
an unusual activation loop conformation, which may provide a
basis for selectivity over Aurora B and other kinases that cannot
adopt this conformation.13 To identify potential off-target
binding activity, a screen of the PerkinElmer General SEP
panel12 was carried out with MLN8054. GABAA α-1
benzodiazapine site binding (IC50 = 330 nM) was the only
potential off-target binding identified.
compd
(nM)
(μM)
(μM)
1
7
1700
33
6000
170
34
>10
>10
5.2
11
0.95
0.22
MLN8054
31
(8)
9
10
1
18
7
2.5
1.5
0.13
0.03
alisertib (10)
a
b
IC50 in HCT116 cells. GI50 values.
pyrimidine amine.9 A screen of substitutions on the pyrimidine
amine demonstrated that submicromolar affinity for Aurora A
could be obtained with aryl substitutions and identified the p-
benzoic acid containing 7 as providing a desirable low
nanomolar affinity in a recombinant Aurora A enzyme assay
(Table 1). As illustrated in Table 1, the selectivity of 7 for
Aurora A over Aurora B was demonstrated in a cellular setting,
by comparing phosphorylation of direct substrates, Aurora A
autophosphorylation (pT288) and Aurora B phosphorylation
of histone H3 (pHisH3) on Ser-10, in HCT116 cells.2 The
compound’s effect on cellular proliferation was measured by a
BrdU incorporation assay. Furthermore, 7 is cell permeable,
stable in human S9 fraction, and soluble as the sodium salt.10
The synthetic route outlined in Scheme 1 illustrates our
approach for the synthesis of 7 and related analogues.
Human tumor cell lines treated with cytotoxic concentrations
of MLN8054 displayed an Aurora A inhibition phenotype,
which included an inhibition of Aurora A autophosphorylation
(pT288), G2/M accumulation, aneuploidy, and increased
apoptosis.2,14 An Aurora B phenotype (a decrease in histone
H3 phosphorylation on Ser10 and >4 N DNA content) could
be observed at concentrations >10-fold above the GI50.
Treatment of nude mice bearing human tumor xenografts
with a single oral dose of MLN8054 (30 mg/kg) similarly
resulted in a phenotype consistent with Aurora A inhibition.
Significant tumor growth inhibition, with no overt toxicity, was
observed in multiple xenograft efficacy models grown in
immunocompromised mice.15
a
Scheme 1. Synthesis of Analogues 7−10
MLN8054 is highly cell permeable (Caco-2, 540 nm/s A-B,
790 nm/s B-A) and is not a substrate of P-gp in transfected
MDCK cells. In vitro metabolism is predominantly through
CYP1A2 and 3A4, and no CYP inhibition is observed at
concentrations up to 100 μM. MLN8054 is highly protein
bound (>98%), and pharmacokinetic parameters in rat (Table
2) include low clearance, a high volume of distribution, a 4 h
Table 2. Pharmacokinetic Parameters in Sprague−Dawley
a
Rat
MLN8054 (8)
alisertib (10)
CL (mL min−1 kg−1
)
20.3
1.48
4.2
10.4
2.21
7.0
Vss (L kg−1
)
a
Reagents and conditions: (a) sodium methoxide, methanol, heat; (b)
T1/2 (h)
HOAc, conc. HCl, NaNO2, EtOAc, KI, H2O, 10 °C; (c) prop-2-ynyl-
carbamic acid tert-butyl ester, PdCl2(PPh3)2, CuI, Et3N, CH2Cl2; (d)
HgSO4/formic acid or conc. HCl/DCM or TFA/H2O; (e) K2CO3; (f)
DMF-DMA/DCM, 35 °C; (g) 6, K2CO3, MeOH, 55 °C.
b
F
(%)
100
124
a
Administered IV (1 mg/kg) as a solution in 10% 2-HP-β-CD.
Sodium salts administered PO (10 mg/kg) as a solution in 10% 2-
b
HP-β-CD with 3.5% NaHCO3 (8) or 1% NaHCO3 (10).
Conversion of the amino-benzophenones 2a−c to their
corresponding aryl iodides allowed for Sonogashira coupling
with a protected propargyl amine to provide 3a−c. Hydration
of the alkyne and deprotection of the amine was followed by
exposure to basic conditions, which promoted cyclization to
provide azepines 4a−c. Conversion to the enamines 5a−c
allowed for pyrimidine ring formation through reaction with
terminal half-life and quantitative oral bioavailability. The
principle route of elimination of MLN8054 is through
metabolism, primarily via hydroxylation and acyl glucuronide
formation. Pharmacokinetic parameters in additional preclinical
models allowed for the prediction of favorable PK parameters
in humans.16
B
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Toxicities observed at the maximum tolerated dose in
Sprague−Dawley (SD) rats given MLN8054 orally for seven
consecutive days included myelosuppression and mucositis,
consistent with the antiproliferative effects of Aurora A
inhibition. Also observed were reversible central nervous
system (CNS) effects, likely attributable to GABAA binding.
In Phase I dose escalation studies in patients with advanced
solid cancers, the observed dose limiting toxicity was reversible
somnolence, again attributed to GABAA binding.17,18 Dose
fractionation of MLN8054 (QID), and coadministration of
methylphenidate, failed to sufficiently mitigate dose limiting
somnolence. Cellular phenotypes in patient skin and tumor
biopsies, consistent with inhibition of Aurora A, were observed
at doses above the maximum tolerated dose.19 These studies
demonstrated the need for a molecule with an improved
therapeutic window with respect to CNS effects. The
pharmacodynamic response demonstrating Aurora A inhibition
in patients treated with MLN8054 indicated that the improve-
ment required with regard to CNS effects might only need to
be modest and that continued optimization of the pyrimido-
benzazepine scaffold was warranted. Additionally, the toxicity
studies in SD rats were qualitatively predictive of CNS effects
observed in humans and allowed us to utilize the rat as a
functional assay for the evaluation of candidate molecules that
may provide this improvement.
Efforts to improve the therapeutic window of MLN8054
focused on attempting to decrease the GABAA binding affinity,
reduce the degree of brain partitioning, and to demonstrate no
discernible CNS effects in the SD rat. Accomplishing those
goals within the pyrimidobenzazepine scaffold would give us
the best opportunity to retain the Aurora A selectivity, oral
bioavailability, and additional favorable properties imparted by
this scaffold. The extent of brain partitioning of an efficacious
dose of MLN8054 (30 mg/kg, PO) and selected analogues was
characterized in nude mice (Table 3). The results suggested
ratio of Aurora A enzyme inhibition to GABAA α-1
benzodiazepine site binding affinity compared to MLN8054
or 9. As illustrated in Table 1, alisertib is significantly more
potent in the enzymatic and cell based Aurora A assays than
MLN8054 or 9 and displays similar selectivity over Aurora B in
cells. Alisertib inhibition of recombinant Aurora A is
competitive with ATP, and it is characterized as a slow, tight-
binding inhibitor (Ki = 0.3 nM, apparent Koff = 2 × 10−4 s−1).
Alisertib is highly selective against an Invitrogen kinase panel
(20/204, ≥30% inhibition),12 and no additional potential off-
target binding activity was identified in the PerkinElmer
General SEP panel.
Alisertib exhibits favorable pharmacokinetic parameters in
the SD rat (Table 2). SD rats were dosed orally with 9 or
alisertib to evaluate their potential to elicit the effects of GABAA
binding. No effects attributable to GABAA binding were
observed. Exposures attained with 9 (AUC0−24 h = 244 μg/
mL·hr, Cmax = 46 μg/mL) and alisertib (AUC0−24 h = 201 μg/
mL·h, Cmax = 48 μg/mL) in these studies were significantly
higher than exposures of MLN8054 (AUC0−24 h= 13.8 μg/mL·
h, Cmax = 5.2 μg/mL) that are capable of eliciting CNS effects in
SD rats. GABAA related effects could, however, be observed
when rats were dosed with a 5 min IV infusion of alisertib,
albeit at peak plasma concentrations significantly higher than
those required for MLN8054 to produce CNS effects.12
Toxicities observed at the maximum tolerated dose in SD
rats given alisertib orally for seven consecutive days were
myelosuppression and mucositis, consistent with Aurora A
inhibition. No effects attributable to GABAA binding were
observed. The mitigation of GABAA mediated effects observed
with 9 and alisertib in the SD rat model provided the basis for a
potential improvement in the therapeutic window in the clinic,
with respect to the somnolence observed with MLN8054. In
addition, alisertib has the potential for further improvement of
this therapeutic window due to its greater potency against
Aurora A compared to 9 and MLN8054.
a
Table 3. Brain Total Exposure in Nude Mice
Nude mice bearing human tumor xenografts treated with a
single oral dose of alisertib (20 mg/kg) displayed a phenotype
consistent with inhibition of Aurora A.4 MLN8054 and alisertib
were evaluated in a Calu-6 human tumor xenograft growth
efficacy model, see Figure 2. Alisertib displayed equivalent to
superior tumor growth inhibition with a lower compound
exposure than that of MLN8054. Alisertib has demonstrated
AUC
plasma
AUC
AUC
b
brain Cmax
(μg/mL)
b
b
compd
brain
ratio
MLN8054 (8)
9
58.2
54.3
62.3
12.5
3.5
0.22
0.06
0.03
2.6
0.93
0.42
alisertib (10)
2.0
a
The sodium salts of 8, 9, and 10 administered PO (30 mg/kg) as a
solution in 10% 2-HP-β-CD with 3.5% NaHCO3 (8 and 9) or 1%
b
NaHCO3 (10). AUC0−8h (μg/mL·h), Ratio of brain AUC0−8 h
/
plasma AUC0−8 h
.
that lower brain partitioning could be achieved while
maintaining similar plasma levels. Compound 9, in which one
of the fluorine substituents on the 7-phenyl ring is replaced
with a methoxy group, displayed a 3-fold brain AUC reduction.
Compared to MLN8054, 9 displays comparable enzymatic and
cellular Aurora A inhibition (Table 1) and has similar binding
affinity for GABAA (IC50 = 150 nM). When an additional
methoxy group was incorporated ortho to the carboxylic acid,
providing alisertib (10),4,11 comparable binding affinity for
GABAA (IC50 = 490 nM) and an additional reduction in mouse
brain partitioning was observed. A similar trend was observed in
the SD rat with brain/plasma AUC ratios for MLN8054 (0.23)
being higher than 9 (0.14) and alisertib (0.07).
Figure 2. Growth inhibition of Calu-6 human lung tumor xenografts as
measured by average tumor volume (mm3). Mice were dosed orally
twice daily for 21 consecutive days with vehicle, 30 mg/kg MLN8054
(8), or 20 mg/kg alisertib (10) as sodium salts. Error bars denote the
standard error of the mean.
While we were unable to diminish GABAA binding potency
with these compounds, alisertib displayed a greater selectivity
C
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significant tumor growth inhibition in multiple human tumor
xenograft models.4,20
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somnolence observed upon administration of alisertib was not
dose limiting. Additionally, pharmacodynamic effects in skin
and tumor biopsies reflecting Aurora A inhibition were
observed at doses below the maximum tolerated dose. These
studies provided support for the continued clinical investigation
of alisertib.
We have identified the pyrimidobenzazepines as a unique
kinase inhibitor scaffold. From this scaffold, MLN8054 (8) was
identified as a potent and selective inhibitor of Aurora A. Off-
target somnolence was identified as the dose limiting toxicity of
MLN8054 in humans. Alisertib (10) was discovered and
identified to have a potentially greater therapeutic window due
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data for compounds 7−
10, kinase selectivity data, and SD rat exposures. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/ml500409n.
(10) Caco-2 cells A-B 580 nm/sec, B-A 640 nm/sec; predicted
CLhep 0.5 L/h/kg; >10 mg/mL aqueous solubility of the sodium salt
of 7.
(11) Claiborne, C. F.; Sells, T. B.; Stroud, S. G. Preparation of
[(phenylpyrimidobenzazepinyl)amino]methoxybenzoic acid deriva-
tives for us as antitumor agents. WO2008063525, May 29, 2008.
(12) See Supporting Information
AUTHOR INFORMATION
■
Corresponding Author
*E-mail todd.sells@takeda.com.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Cindi Barrett, Cindy Q. Xia, Chuang Lu, Vinita
Uttamsingh, Sandeepraj Pusalkar, and Hong Zang for assay
support.
ABBREVIATIONS
■
Aur A, Aurora A; BrdU, 5-bromo-2′-deoxyuridine; GABAA,
gamma-aminobutyric acid ionotropic receptor; LE, ligand
efficiency; MDCK, Madin−Darby canine kidney
D
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