Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity

Article abstract of DOI:10.1021/ml100158s

A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzym

Full text of DOI:10.1021/ml100158s

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Discovery of a Potent Inhibitor of Anaplastic Lymphoma
Kinase with in Vivo Antitumor Activity
Gregory R. Ott,* Rabindranath Tripathy,* Mangeng Cheng, Robert McHugh,
Andrew V. Anzalone, Ted L. Underiner, Matthew A. Curry, Matthew R. Quail, Lihui Lu,
Weihua Wan, Thelma S. Angeles, Mark S. Albom, Lisa D. Aimone, Mark A. Ator,
Bruce A. Ruggeri, and Bruce D. Dorsey
Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380
ABSTRACT A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one deri-
vatives within the diaminopyrimidine class of kinase inhibitors were identified that
target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an
isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein
NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15,
which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety,
activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against
ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against
the structurally related insulin receptor, is orally bioavailable in multiple species, and
displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor
xenografts in Scid mice.
KEYWORDS Anaplastic lymphoma kinase inhibitor, ALK, anaplastic large cell
lymphoma, ALCL
pproximately 60% of human anaplastic large cell
lymphoma (ALCL) cases are associated with a t(2;5)
(p23;q35) chromosome translocation.1,2 The t(2;5)
cancers, inhibition of ALK with a selective small molecule
represents a potentially viable enhancement to the clinical
outcome of patients with well-defined ALK-mediated can-
cers. As a result, interest in small-molecule ALK inhibitors has
surged, and a plethora of unique chemical scaffolds (Figure 1)
have been disclosed including indolocarbazole (1),3 tetrahydro-
pyrido[2,3-b]pyrazine (2),8 pyridone (3),9 dianilinopyrimidine
(4),4 1H-pyrrolo[2,3-d]pyrimidine (5),10 and aminopyridine (6)5
pharmacophores.11 -13
As noted, ALK is a member of the insulin receptor (IR)
family, displaying high sequence homology (>90%) to IR
within the kinase catalytic domain. The biological implica-
tions of inhibiting IR with a small-molecule kinase inhibitor
have been sporadically reported, although recent reports
have demonstrated compound-dependent fluctuation in
glucose homeostasis in preclinical animal studies.10,14,15
Therefore, obtaining adequate selectivity may provide a
more favorable safety profile. Herein, we report the identi-
fication of a novel ALK inhibitor that is potent in enzymatic
and cellular assays and displays >40-fold selectivity against
the structurally related IR. Furthermore, this lead inhibitor
induces pro-apoptotic caspase activation and displays selec-
tive cytotoxicity against ALK-positive ALCL cells. Acceptable
oral bioavailability in multiple species was realized along
A
translocation contains the N-terminal portion of nucleophos-
min (NPM) gene, a nuclear phosphoprotein, fused to the
catalytic domain of anaplastic lymphoma kinase (ALK) gene.
The NPM-ALK fusion gene encodes for an 80 kDa NPM-ALK
chimeric oncoprotein with constitutively active ALK tyrosine
kinase activity, which plays a key role in lymphomagenesis by
aberrant phosphorylation of intracellular substrates.1,2 This
activity is directly implicated in the pathogenesis of ALCL, and
inhibition of ALK could markedly impair the growth of ALK-
positive lymphoma cells.1-5 Furthermore, various isoforms of a
fusion gene comprised of portions of the echinoderm micro-
tubule-associated protein-like 4 (EML4) gene and the ALK gene
were identified in NSCLC cells.6 The EML4-ALK fusion tran-
script was detected in approximately 3-7%ofNSCLCpatients
examined.6 Experimental evidence from in vitro and in vivo
studies demonstrated oncogenic transforming activity of the
EML4-ALK fusion proteins and reinforced the pivotal role of
EML4-ALK in the pathogenesis of NSCLC in humans.6 More-
over, recent studies have implicated various mutations of the
ALK gene in both familial and sporadic cases of neuroblas-
toma.7 ALK mutations in neuroblastoma cells resulted in
constitutive ALK phosphorylation and attenuation or inhibi-
tion of ALK by siRNA, and small-molecule ALK inhibitors
resulted in profound growth inhibition in those cell lines.7
Because of the strong link of aberrant expression and activa-
tion of ALK with the onset and progression of ALK-positive
Received Date: July 2, 2010
Accepted Date: August 23, 2010
Published on Web Date: September 01, 2010
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with in vivo antitumor efficacy when dosed orally in ALK-
positive ALCL tumor xenografts in Scid mice.
In our current pursuit of small-molecule ALK inhibitors,
we identified the novel 7-amino-1,3,4,5-tetrahydrobenzo-
[b]azepin-2-one derivative 7 (Table 1) within the dianilino-
pyrimidine class that displayed potent activity against ALK
(IC50=15 nM) with only a 1.5-fold margin against IR. Impor-
tantly, inhibition of NPM-ALK autophosphorylation in ALK-
positive ALCL cells (Karpas-299) was quite robust (IC50 = 30
nM). Early structure-activity relationships (SAR) identified the
benzamide functionality as a key potency determinant for ALK.
Shifting the benzamide one carbon to provide 8 resulted in
substantial loss in ALK potency, whereas the introduction of a
2-amino-N-methylsulfonamide (9) provided a boost in ALK
activity (IC50 = 1 nM), although only a slight improvement to
cellular activity (IC50=20 nM). IR selectivity for 9 increased to
10-fold. Surveying several kinase active saturated/partially satu-
rated 2-amino-carboxamide substructures16,17 to gauge the im-
pact on potency and selectivity, the aryl ring was replaced with
cis-3-amino-bicyclo[2.2.1]hept-5-ene-2-carboxamide (cf. 10),
which resulted in a slight drop-off in ALK activity and only
5-fold IR selectivity, although acceptable ALK cell transla-
tion was noted. cis- and trans-2-Aminocyclohexanecarboxa-
mide derivatives 11 and 12 provided no advantage. Early
screening for pharmacokinetic (PK) parameters identified
Figure 1. Small-molecule ALK inhibitors.
Table 1
a IC50 values are reported as an average of g3 determinations; for values ( SD, see the Supporting Information; NT, not tested. b IC50 values are
reported as a mean of at least two determinations.
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Table 2
a IC50 values are reported as an average of g determinations; for values ( SD, see the Supporting Information. b IC50 values are reported as a mean of
at least two determinations.
members of this series displaying modest oral bioavailabil-
ity; 7, 9, and 10 displayed 9, 11, and 13% oral bioavail-
ability in rat, respectively.
substituents18 at either the 6-position or the 8-position of the
benzazepinone as preferable for selectivity. These structural
modifications were combined with the 5-chloro-4-aminopyrimi-
dine scaffolds A, B, and C (Tabl e 2). The 6-methoxy derivative 13
and the 8-methoxy derivative 14 both provided acceptable ALK
potency with 14 having about 2-5-fold improved activity rela-
tive to 13, at the expense of IR selectivity. This trend was appa-
rent for all scaffolds tested. Importantly, 13 displayed 20-fold
separation of ALK versus IR, an improvement relative to parent
7. Incorporating these 6-methoxy- and the 8-methoxybenzaze-
pinones on the single isomer (1S,2S,3R,4R)-aminobicyclo-
[2.2.1]hept-5-ene-2-carboxylic acid amide scaffold B19 gave 15
and 16. Although 16 was 2-fold more potent in the isolated
On the basis of the promising SAR with respect to enzy-
matic ALK activity, cellular inhibition, and modulation of IR
activity, we sought to further optimize IR selectivity and
improve upon the modest oral bioavailability on the 2-ami-
nobenzamide, 2-aminobenzenesulfonamide, and the 3-amino-
bicyclo[2.2.1]hept-5-ene-2-carboxamide scaffolds through
modification of the 7-amino-1,3,4,5-tetrahydrobenzo[b]aze-
pin-2-one. Toward this end, while maintaining acceptable
potency, we identified the ethyl substituent on the azepinone
nitrogen for improved PK parameters and ortho-methoxy
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Scheme 1. Synthesis of Compound 15
Table 3. PK Parameters of 15a
PK parameters Scid mouse
iv
rat
dog
dose (mg/kg)
1/2 (h)
1.0
0.3
1.0
0.8
13
20
0.9
1276
1.0
1.1
22
58
2.1
t
Cl (mL/min/kg)
% Cl/hepatic blood flow
Vd (L/kg)
37
41
0.9
AUC (ng h/mL)
446
po
773
dose (mg/kg)
10.0
0.25
2.4
1406
32
5.0
10
t
t
max (h)
1/2 (h)
0.8
2.2
1.1
1.6
2482
31
AUC (ng h/mL)
F (%)
4088
64
a Determinants of three for each dosing group, average value; for
values ( SEM, see the Supporting Information.
required to induce measurable cytotoxicity and caspase activa-
tion.3 Therefore, the calculated cytotoxicity EC50 values (∼200-
267 nM) are close to the cellular IC80-90 values. In contrast, 15
had minimal growth inhibition on ALK-negative K562 cells at
concentrations up to 1 μM (Supporting Information, Figure 1A),
suggesting that at the concentrations studied, 15 exerts growth
inhibition on ALK-positive ALCL cells primarily through inhibit-
ing NPM-ALK activity. The in vitro cytotoxicity of 15 in cells was
also assessed via measurement of caspase 3/7 activity. Treat-
ment of ALK-positive cell lines with 15 led to concentration-
related caspase 3/7 activation (Supporting Information,
Figure 1B). In contrast, no caspase 3/7 activation was detected
in K562 cells treated with 15. These data indicate that 15 exerts
in vitro cytotoxicity on ALK-positive ALCL cells mainly through
inhibiting NPM-ALK activity. As a further assessment of selec-
tivity, compound 15 was profiled in the Ambit KINOMEscan
against 402 kinases.24 At screening concentrations of 1 and
0.1 μM (roughly 100- and 10-fold above the ALK IC50), selecti-
vity scores for 90% inhibition [S(90) values]24,25 of 0.090 and
0.015, respectively, were observed suggesting that off-target
kinase activity is minimal and that the induction of pro-apopto-
tic proteins and antiproliferative effects of 15 is primarily driven
by inhibition of ALK.
Compound 15 was profiled in three species for PK para-
meters (Table 3). Following iv dosing, clearance in Scid
mouse (37 mL/min/kg) was 41% of hepatic blood flow,26
while the clearance observed in rat was more moderate at
20% of liver blood flow. Clearance in dog was the highest as a
percentage of hepatic blood flow (58%). The volume of
distribution was near unity for rodents with a higher value
observed in dogs. Following oral dosing, rapid absorption
was observed in Scid mouse with a more extended tmax for
rat and dog. Oral bioavailability was 2-fold higher in rats than
dog or Scid mice. On the basis of PK, potency, and selectivity,
15 advanced to in vivo PK/pharmacodynamic (PD) and
antitumor xenograft efficacy studies.
enzyme assay, near equivalent results were obtained in the cell
assay.20 Importantly, compound 15 displayed improved IR
selectivity to that observed for compound 13. Surveying a series
of sulfonamide derivatives (17-20), low nanomolar ALK inhibi-
tion could be achieved with potent activity in cellular inhibition of
NPM-ALK autophosphorylation. Unfortunately, improved IR
selectivity was not obtained with these modifications with
margins ranging from 4-fold for 20 to 9-fold for 17 and 18. On
the basis of these results, compound 15 displayed the most
promising balance between ALK activity (enzyme and cells) and
IR activity. Furthermore, when assessed for PK parameters, 15
displayed favorable attributes (vide infra).
The synthesis of compound 15 followed the sequence
outlined in Scheme 1. Nitration of benzo[b]azepinone 2121
controlling the stoichiometry of the nitrating reagent22 read-
ily gave the desired product as a mixture of nitro regiomers
separable by silica gel chromatography. Alkylation of the
azepinone nitrogen gave 23. Reduction provided 7-amino-
benzo[b]azepinone 24. The β-aminoamide derivative was
prepared from (1S,2S,3R,4R)-3-methoxycarbonylamino-
bicyclo[2.2.1]hept-5-ene-2-carboxylic acid 25.23 Formation
of a mixed anhydride and displacement with ammonia
provided the amide 26. Deprotection of the amine to give
27 was followed by a highly convergent assembly of the
target. The addition of 27 to 2,4,5-trichloropyrimidine pro-
vided 28, which was then treated with 24 using an acid-
mediated addition protocol to provide 15 in 65% yield.
The effects of 15 on the proliferation and survival of ALK-
positive ALCL cells (Karpas-299 and Sup-M2) and ALK-negative
cells (K562, a leukemia cell line) in culture were evaluated by
MTS and caspase 3/7 activation assays. Compound 15 displayed
concentration-dependent growth inhibition of Karpas-299 and
Sup-M2 cells in culture, with the extent of growth inhibition
consistent with cellular inhibition of NPM-ALK phosphorylation
in these cells (Supporting Information, Figure 1A). Because of
extremely high levels of NPM-ALK expressed in ALCL cells, at
least 80-90% inhibition of NPM-ALK phosphorylation in cells is
Following oral administration of 15 (30 mg/kg) in vehicle
(PEG400), inhibition of NPM-ALK autophosphorylation in
tumor lysates from ALK-positive ALCL tumor xenografts
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(Figure 2B). Relative to the single dose PK/PD study, an approxi-
mately 2-fold increase in compound levels was observed in both
plasma and tumors with 12 days of b.i.d. dosing. The result is
consistent with the observation that the antitumor efficacy in
this model is an area under the curve (AUC) driven event, in
which sustained target inhibition is required to achieve signifi-
cant tumor growth inhibition and tumor regression.
In summary, novel small-molecule inhibitors of ALK within
the diaminopyrimidine class have been identified. Optimization
of potency, off-target selectivity, and PK parameters led
to the identification of compound 15, which displayed favorable
potency in an ALK enzymatic assay as well as a cellular assay
measuring oncogenic NPM-ALK autophosphorylation. Further-
more, oral administration of compound 15 to mice bearing ALK-
positive ALCL sc xenografts resulted in complete/near-complete
regressions. Compound 15 advanced to late preclinical candi-
date evaluation, benchmarking the program with a defining tool
compound. Further optimization of this structural class will be
reported in future publications.
SUPPORTING INFORMATION AVAILABLE Procedures for
the preparation of 15, analytical data for compounds 7-20, and
procedures for in vitro and in vivo assays. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: *To whom correspondence should be
addressed. E-mail: gott@cephalon.com (G.R.O.) and rtripath@
cephalon.com (R.T.).
ACKNOWLEDGMENT We thank Emily Kordwitz for obtaining
specific rotations and analytical HPLC measurements and James
Haley and Dr. Renee Roemmele for assistance in preparation of
intermediates.
Figure 2. (A) In vivo antitumor efficacy of 15 following oral dosing
in SUP-M2 tumor xenografts. (B) Compound levels in plasma and
tumor lysates at 2 h postfinal dose.
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