Potent and selective inhibitors of CK2 kinase identified through structure-guided hybridization

Article abstract of DOI:10.1021/ml200257n

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a] pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

Full text of DOI:10.1021/ml200257n

Letter
pubs.acs.org/acsmedchemlett
Potent and Selective Inhibitors of CK2 Kinase Identified through
Structure-Guided Hybridization
James E. Dowling,* Claudio Chuaqui, Timothy W. Pontz, Paul D. Lyne, Nicholas A. Larsen,
Michael H. Block, Huawei Chen, Nancy Su, Allan Wu, Daniel Russell, Hannah Pollard, John W. Lee,
Bo Peng, Kumar Thakur, Qing Ye, Tao Zhang, Patrick Brassil, Vicki Racicot, Larry Bao,
Christopher R. Denz, and Emma Cooke
AstraZeneca, Oncology Innovative Medicines Unit, 35 Gatehouse Drive, Waltham, Massachusetts 02145, United States
S
* Supporting Information
ABSTRACT: In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]-
pyrimidine hits identified by kinase-focused subset screening as starting points for the
structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2.
The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation
in vitro are described.
KEYWORDS: CK2, casein kinase, structure-based design, pyrazolo[1,5-a]pyrimidine
asein Kinase 2 (CK2) is a highly conserved and
ubiquitously expressed serine/threonine kinase, which
inhibitor of CK2 which exhibits single-agent activity in xeno-
graft models and is currently in clinical trials for the treat-
ment of cancer.13
There remains a need for additional novel agents with the
necessary balance of potency, selectivity, druglike properties,
tolerability, and efficacy that can successfully exploit the critical
function of CK2 in cancer-linked pathways for the treatment of
disease. Herein we disclose the discovery of a series of potent
and selective inhibitors of CK2 derived from the pyrazolo[1,5-a]-
pyrimidine scaffold.
As an alternative to conventional high throughput screening
(HTS), we employed a kinase-focused subset screening
approach. A library of ≈10K compounds was assembled from
the AstraZeneca collection by applying general kinase binding-
site and target-specific structural bioinformatic filters. Single point
screening of the subset gave ≈2500 compounds with kinase inhi-
biton greater than 60% at 10 μM. These hits were consolidated
further by application of physical property, in vitro ADME
(absorption, distribution, metabolism, and excretion), and
kinase selectivity filters to give ≈1400 compounds selected for
full CK2 α′ IC50 determination using an in vitro mobility shift
microfluidics assay.14 Among the hits characterized in this way, a
series of 3-cyano-5-aryl-7-amino-pyrazolo[1,5-a]pyrimidines
(Table 1, 1a−h) exhibited submicromolar potency and high
C
exists as a tetrameric complex containing two catalytic (α or α′)
and two regulatory (β) subunits.1 CK2 is regarded as a
constitutively active kinase with broad function, although more
recent evidence suggests that CK2 can be regulated by growth
factors such as IL-6 and epidermal growth factor (EGF).2,3
The importance of CK2 for cell viability has been demonstrated
by genetic studies, showing that suppression of the α or β subunits
leads to embryonic lethality in mice, while genetic silencing of
the α′ subunit results in viable offspring, but with males exhi-
biting defects in spermatogenesis leading to infertility.4,5 CK2
regulates several key oncogenic signaling pathways, including PI3K
(phosphatidylinositol 3-kinase), AKT (protein kinase B), NFκB
(nuclear factor kappa-light-chain-enhancer of activated B cells),
and Wnt (wingless type MMTV integration site family).6−8
Targeted overexpression in transgenic animal models results in
neoplastic growth9 and administration of antisense oligodeoxy
nucleotides against CK2α induced concentration-dependent
tumor shrinkage in a human prostate cancer xenograft model.10
A variety of ATP-competitive, small molecule inhibitors of
CK2 have been identified.11 These include various polyhy-
droxylated aromatic compounds, such as emodin and quercetin,
polyhalogenated compounds, such as DRB (5,6-dichlororibo-
furanosylbenzimidazole) and TBB (4,5,6,7-tetrabromo-1H-
benzotriazole), as well as the indolo[1,2-a]quinazoline
derivative IQA.12 More recently, researchers from Cylene
have disclosed CX-4945, a selective, orally available small molecule
Received: October 27, 2011
Accepted: January 24, 2012
Published: January 24, 2012
© 2012 American Chemical Society
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Table 1. CK2 Biochemical and Cellular Potency for Compounds 1a−h and 3a−h
a
a
cpd
R5
R7
CK2 IC50 (μM)
HCT-116 GI50 (μM)
1a
1b
1c
1d
1e
1f
2-thienyl
NH2
NH2
NH2
NH2
0.10
0.18
>30
>30
ND
ND
ND
14
Ph
p-MeO-Ph
0.058
0.43
p-F-Ph
2-thienyl
cyclopropylamino
0.46
p-MeO-Ph
cyclopropylamino
0.078
0.052
0.25
1g
1h
3a
3b
3c
3d
3e
3f
p-MeO-Ph
1-methyl-1H-pyrazol-3-ylamino
cyclopropylamino
4.5
b
4-methoxy-3-pyridyl
6-acetamidoindol-1-yl
6-acetamidoindazol-1-yl
16 (15)
b
cyclopropylamino
0.010
0.026
<0.003
0.004
0.27
0.53 (1.0)
b
cyclopropylamino
3.7 (5.0)
b
6-acetamido-pyrrolo[3,2-b]pyridin-1-yl
6-acetamidoindolin-1-yl
cyclopropylamino
3.0 (2.1)
b
cyclopropylamino
0.53 (0.73)
6-acetamido-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)-
6-acetamido-(1,2,3,4-tetrahydroquinolin-7-yl)-
6-acetamido-5-methyl-indol-1-yl
cyclopropylamino
ND
ND
>30
cyclopropylamino
0.24
3g
3h
cyclopropylamino
0.079
0.024
b
6-acetamido-indol-1-yl
1-methyl-1H-pyrazol-3-ylamino
0.46 (0.56)
a
b
Mean value of three experiments. Deviations were within < 25%. SW480 Alamar Blue proliferation assay; ND = not determined.
ligand efficiency15 (1a; LE = 0.4). Preliminary SAR studies for
1a−h suggested that electron-rich aromatic and heteroaromatic
systems at C5 and substitution of the C7 amine with small
carbo- and heterocyclic substituents enhanced potency. Neither
the des-cyano analogue of 1a nor the 2-methyl derivative of
1f (not shown) exhibited activity toward CK2 (>30 μM).
However, despite the encouraging biochemical activity exhi-
bited by this series, potency in Alamar Blue cell proliferation
assays14 was modest (1g, HCT-116 GI50 = 4.5 μM).
During the course of this effort, a disclosure16 by other
researchers described a series of CK2 inhibitors (2) with
pharmacophoric elements designed to establish interactions
with Lys68, Asp175, and a previously observed structural water
molecule.12 We sought to couple these insights with further
modifications identified in our own work. In silico modeling of
1a with compound 2 (Figure 1) suggested the introduction of
acetamide-containing 5,6-fused ring systems at the C5 position
of the pyrazolo[1,5-a]pyrimidine core to give conformationally
constrained hybrid structures such as 3a (Figure 2).
To test this design hypothesis, we prepared a series of
3-cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines substi-
tuted at the 5-position with various 5,6- and 6,6-fused ring
heterocycles (Table 1). Gratifyingly, indole 3a (CK2 IC50
=
10 nM) demonstrated that a planar, bicyclic structure is
accommodated by the receptor and that the aniline NH of 2 is
less important for its activity. Introduction of nitrogen into
the five-membered ring, as with indazole 3b, led to a modest
reduction in potency whereas 4-azaindole derivative 3c
exhibited enhanced enzymatic potency relative to 3a. Partial
saturation of the five-membered ring, as with indoline 3d,
preserved activity; however, partially saturated 6,6-fused
analogues such as benzoxazine 3e and tetrahydroquinoline 3f
are 10-fold less active. Substitution adjacent to the acetamide, as
in 5-methyl derivative 3g, is disfavored, presumably due to
destabilization of the interaction with Lys68 and Asp175 via
increased out-of-plane rotation. Deletion of the 3-cyano group
Figure 1. Overlay of screening hit 1a with compound 2 illustrating
their computationally derived binding poses in CK2.
in 3a (not shown) led to a significant reduction in enzymatic
activity (CK2 IC50 = 2.6 μM).
Cellular potency for this series was determined using
mechanistic and phenotypic end points. Depletion of cellular
levels of pAKTS129, a direct substrate of CK2 believed to hyper-
activate the AKT pathway,7 was measured in Western blot and
ELISA (enzyme-linked immunosorbent assay) formats (Figure 3).17
Consistent with effects on prosurvival signaling, 3a induces
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ACS Medicinal Chemistry Letters
Letter
groups. Analysis of the ATP-binding site suggested that several
residues in the solvent channel are potentially disposed to form
favorable interactions with polar groups and may also serve as
selectivity determinants against other kinases. On the basis of
the SAR for the indole and related heterocycles, we felt that we
could optimize cellular potency and physical properties through
modifications in other portions of the structure and potentially
employ the indoline or 4-azaindazole rings to address in vitro
ADME issues should they persist.
Figure 2. Design of fused-ring analogue 3a.
Replacement of the cyclopropyl group of 3a with four- and
five-membered heterocycles is well-tolerated; N-methylpyrazole
3h exhibits cellular potency equivalent to that of 3a (pAKT
IC50 = 16 nM) while oxetane 4a is 4-fold less active (Table 2).
Hydrophilic substituents at the terminus of two- and three-
atom spacers preserved enzymatic activity and enhanced
physical properties but led to significant reduction in cellular
potency. Despite possessing comparable enzymatic activity with
3h, 1-hydroxybutyl derivative 4b and dimethylamino-propyl
derivative 4e exhibit a 10- and 100-fold drop in potency in the
mode of the action assay (pAKTS129 ELISA), respectively. The
permeability of 3a in MDCK-MDR1 (multidrug resistance
protein 1) cells is moderate (A-B Papp = 22 × 10−6 cm/s)
with low efflux characteristics (efflux ratio = 1.4). Conversely,
both 4c and 4f exhibit low A-B permeability (A-B Papp ≤5 ×
10−6 cm/s) and high efflux potential (efflux ratio = 17) in
MDR1 overexpressing LLC/PK1 cells. In addition, compound
4f exhibits virtually no exposure (AUC = 0.065 μM·h) follow-
ing administration of a single 10 mg/kg oral dose in the rat.
These results suggest that membrane permeation in this series
is impaired when lipophilicity is reduced such that log D < 2.9,
and the effect may be compounded by the presence of a basic
amine.
apoptosis, as measured by caspase activation in HCT-116 cells
(not shown). Indole 3a and indoline 3d possess comparable
antiproliferative activity. However, for reasons not clear to us,
indazole 3b and 4-azaindole derivative 3c exhibit a 30−100-fold
drop in phenotypic potency relative to the effects observed in
the pAKTS129 ELISA assay. Comparable potency was exhibited
in a SW480 cell proliferation assay.
The physical properties for 3a−h are poor, with low aqueous
solubility, high protein binding in human plasma, and moderate
lipophilicity (3a; solubility <10 μM at pH 7, fu <1%, log D = 3.3).
As a consequence, the in vivo pharmacokinetic profile for 3a
following a single oral 10 mg/kg dose in the rat is characterized
by poor oral bioavailability (F = 5%) and low clearance (Cl =
10 mL/(min/kg)). In addition, 3a possesses moderate activity
at the hERG (human Ether-a-go-go Related Gene) ion channel
(hERG IC50 = 8.6 μM) and inhibits CYP1A2 (cytochrome
p450 isozyme) with an IC50 = 0.1 μM. Conversely, indazole 3b
and indoline 3d exhibit reduced hERG channel activity (hERG
IC50 >33 μM) while 4-azaindole 3c is devoid of CYP1A2
activity (CYP1A2 IC50 > 20 μM).
We next attempted to improve the physical properties in 3a
by replacing the N7 cyclopropyl substituent with hydrophilic
Figure 3. (a) Concentration-dependent depletion of pAKTS129 in HCT-116 cells at 3 h and 24 h by 3a, as measured by Western blot analysis. (b)
Inhibition of pAKTS129 in DLD-1 cells by 3h as determined by ELISA. (c) Depletion of pAKTS129 in DLD-1 cells upon treatment with 3h at 24 h as
determined by Western blot.
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Table 2. CK2 Biochemical and Cellular Potency and Physical Property Data for Indoles 4a−4i
a
a
a
cpd
R7
R6
AcNH
CK2 IC50 (μM)
pAKT IC50 (μM)
HCT-116 GI50 (μM)
log D
sol (μM) Hu PPB Fu (%)
b
4a
4b
4c
4d
4e
4f
oxetan-3-yl
0.004
0.030
0.03
0.057
0.19
0.46
0.78
1.2
2.2 (2.5)
2.2
2.6
1
8
12.4
4.1
11
4-hydroxybutyl
AcNH
AcNH
AcNH
AcNH
AcNH
AcNMe
HOCH2
2.8
b
2-morpholinoethyl
2-(pyrrolidin-1-yl)ethyl
3-(dimethylamino)propyl
3-(pyrrolidin-1-yl)propyl
cyclopropyl
>30
ND
2.2
2
0.04
ND
15
5.6
10
b
0.030
0.018
0.011
0.12
25
1.6
750
>1000
<1
b
0.86
0.034
0.83
0.083
13
1.8
6.7
2.5
1.9
1.8
4g
4h
4i
ND
10.1
16.4
2.9
cyclopropyl
3.1
<1
cyclopropyl
MeSO2CH2
0.007
2.5
<1
a
b
Mean value of at least three experiments. SW480 Alamar Blue cell proliferation assay; ND = not determined.
Table 3. CK2 Biochemical and Cellular Potency for 5a−f
a
a
a
cpd
R1
CK2 IC50 (nM)
pAKT IC50 (μM)
HCT-116 GI50 (μM)
b
5a
5b
5c
5d
5e
5f
Me
H
6
5
0.027
0.077
0.50
0.7 (1.1)
b
0.7 (0.7)
b
2-hydroxyethyl
3-hydroxypropyl
CH2CH2CO2Me
CH2CH2CO2H
<3
<3
15
<3
2.7 (4.5)
b
0.21
2.3 (3.2)
b
ND
6.6
3.1
ND
a
b
Mean value of at least three experiments. SW480 Alamar Blue cell proliferation assay; ND = not determined.
We next focused on modifying the acetamide to address the
inhibitor bound as anticipated with N2 of the pyrazolo[1,5-a]-
pyrimidine core and the C7 NH interacting at the hinge region
of the ATP binding pocket.17 As indicated in Figure 4, the
energetic penalty associated with adopting the cis- conforma-
tion of the acetamide is compensated by a network of hydrogen
bonding interactions with Lys68 and Asp175 via the carbonyl and
NH, respectively. Moreover, a buried water molecule in the
vicinity of the gatekeeper residue (Phe113) is coordinated by the
acetamide carbonyl (2.7 Å) and the cyano group (3.0 Å). The
propanoic acid adopts an extended conformation in which the
β-CH2 group makes a hydrophobic contact between Gly46 and
the side-chain of Val53 and positions the carboxylate group at
the solvent-accessible surface.
CK2 shares a high degree of binding site homology with a
range of kinases, including GSK-3β (glycogen synthase kinase
3 beta) and CDK2 (cyclin-dependent kinase 2), targets for which
pyrazolo[1,5-a]pyrimidine derivatives are reported to have
affinity.18 Compound 3a was shown to be highly selective when
tested against a panel of 324 kinases (Ambit Biosciences, San
Diego, CA),19 at a concentration of 1 μM. From the 16 kinases
with inhibition >50%, we selected four for subsequent IC50
determinations (Table 4). Introduction of nitrogen reduces
affinity toward GSK-3β, as in indazole 3b (IC50 = 0.7 μM) and
observed drop-off in cellular potency and the low bioavailability
of nonbasic compounds. Substitution of the acetamide NH of
3a, to give N-methylacetamide 4g, preserved enzymatic and
cellular activity but led to reduced stability when incubated with
rat liver microsomes (Clint = 100 mL/(min/kg)). Installation of
a hydroxymethyl group (4h) led to a significant reduction in
enzymatic and cellular potency. Sulfone 4i exhibited high
potency in the biochemical assay and moderate activity in the
pAKT assay but lacked any significant antiproliferative effect.
These results also confirm the pivotal role of the acetamide
carbonyl of 3a and suggest that the NH is less critical and that
other variations on the donor−acceptor group may be tolerated.
As an alternative to the solvent channel approach, we
explored the use of a “reversed” indole scaffold to incorporate
polar functionality (Table 3). The N1-methyl analogue (5a)
and the unsubstituted 5b are potent CK2 inhibitors and exhibit
submicromolar activity in the proliferation assay. More ela-
borate substitution at this position gave compounds (5c−f)
with high enzyme activity but weaker effects in the mode of
action (pAKTS129) and phenotypic assays.
An X-ray cocrystal structure determination of 5f with
recombinant human CK2 at 2.2 Å resolution showed the
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4-azaindole 3c (IC50 = 1.0 μM). The presence of a basic group
in the solvent channel region, as in 4e, reduces GSK-3β (IC50
=
2.6 μM) and Dyrk1 (dual-specificity tyrosine phosphorylation-
regulated kinase 1) activity (IC50 = 2.6 μM). Members of the
series exhibit a high degree of HipK2 (homeodomain-inter-
acting protein kinase 2) potency, although substitution of the
“reversed” indole NH reduces this affinity (5f, HipK2 IC50
=
0.57 μM). These data suggest that further enhancement of CK2
selectivity in this scaffold may be achieved through appropriate
combination of the diversity elements identified thus far.
Synthesis of 5-acetamidoindole and related analogues (3a−h,
4a−i) was accomplished using a convergent approach (Scheme 1)
that commenced with installation of the requisite amine by
displacement of the 7-chloro group in 5,7-dichloro-
3-cyanopyrazolo[1,5-a]pyrimidine (6). Replacement of the
5-chloro substituent in 7 was accomplished by Pd2(dba)3
(tris(dibenzylideneacetone)dipalladium(0))-mediated coupling
via the NH of the appropriate fused ring system.20 In cases
where the acetamide was not yet present in the coupling
partner, the appropriate nitro precursor precursor (8, 11, 13)
was utilized followed by subsequent reduction (to give 9, 12,
and 14, respectively) and acetylation. Similarly, methylsulfonyl-
methyl derivative 4h was prepared from 4g followed by
mesylation and displacement with MeSO2Na. Synthesis of
“reversed” indoles (5a−f) was carried out beginning with the p-
toluenesulfonyl derivative of 5-nitroindole (15) followed by
conversion to mercury(II)acetate derivative 16 and subsequent
treatment with borane to afford boronic acid 17.
Suzuki coupling of the latter with 7 afforded 18, which,
following functional group manipulation, gave a mixture of 5a
and 5b. Alkylation of the indole NH could be accomplished to
deliver 5c and 5d. Conjugate addition of 5b with methyl
methacrylate furnished 5e, which afforded 5f following ester
hydrolysis (Scheme 2).
In conclusion, we have identified a series of potent and
selective inhibitors of CK2 kinase using structure-based
hybridization of an early screening hit with a literature scaffold.
Enhancement of physical properties in the 6-acetamidoindole
series (3a) was achieved by modification of the N7 substituent
Figure 4. X-ray cocrystal structure determination of 5f with huCK2 at
2.2 Å. Bound water molecules are shown as spheres.
Table 4. Kinase Selectivity Data for 3a and Related
Compounds
GSK-3β IC50
(μM)
HipK2 IC50
(μM)
Dyrk1 IC50
(μM)
CDK2 IC50
(μM)
cpd
3a
3b
3c
4e
4g
5b
5f
0.13
0.7
1.0
2.6
1.4
0.25
6
0.03
0.05
0.8
26
>30
>30
>30
>30
14
0.02
1.7
0.02
0.06
2.6
<0.003
<0.003
0.57
0.4
0.06
5.4
>30
a
Scheme 1
a
Reagents and conditions: (a) R7-NH2, EtOH, 25 °C; (b) Pd(OAc)2, Xantphos, Cs2CO3, DMA (N,N-dimethyl acetamide)/H2O (4:1), 150 °C,
microwave, 0.5 h; (c) Pd2(dba)3, Xantphos, Cs2CO3, DMA/H2O (4:1), 150 °C, microwave, 0.5 h; (d) Pd2(dba)3, Xantphos, Cs2CO3, 1,4-dioxane, 150 °C,
microwave, 0.5 h; (e) H2, Pd/C; (f) Ac2O, pyridine, 25 °C; (g) DIEA (N,N-diisopropylethylamine), MsCl, THF; (h) KI, MeSO2Na, DMF, 25 °C.
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Letter
a
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Scheme 2
(5) Buchou, T.; Vernet, M.; Blond, O.; Jensen, H. H.; Pointu, H.;
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a
Reagents and conditions: (a) TsCl, Bu4NHSO4, PhMe, 50% aq
NaOH; (b) Hg(OAc)2, HOAc, HClO4; (c) BH3, H2O; (d) Pd(PPh3)4,
Na2CO3, 1,4-dioxane, 100 °C, 3 h; (e) H2, Pd/C, DMF/MeOH;
(f) Ac2O, pyridine, 25 °C; (g) Cs2CO3, MeOH, THF; (h) [(3-
bromoethyl)oxy](1,1-dimethylethyl) dimethylsilane, K2CO3, DMF,
100 °C, microwave; (i) HCl (4.0 M in 1,4-dioxane), 25 °C; (j) [(3-
bromopropyl)oxy](1,1-dimethylethyl)dimethylsilane, K2CO3, DMF,
100 °C, microwave; (k) methyl acrylate, DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene), MeCN, 25 °C; (l) LiOH, THF,
MeOH, H2O, 25 °C.
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Proffitt, C.; Streiner, N.; Trent, K.; Rice, W. G.; Ryckman, D. M.
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but had a deleterious effect on cellular potency. Kinase selec-
tivity profiling has revealed 3a to be highly selective and has
identified structural features that further reduce off-target
effects. Exploitation of the crystallographically determined bind-
ing mode of 5f for enhancement of primary target potency
and kinase selectivity will be described in a subsequent
communication.
(14) See Supporting Information.
(15) Bembenek, S. D.; Tounge, B. A.; Reynolds, C. H. Ligand
efficiency and fragment-based drug discovery. Drug Discovery Today
2009, 14, 278−283. LE (ligand efficiency) = −log(CK2 IC50)/
number of heavy atoms.
(16) Nie, Z.; Perretta, C.; Erickson, P.; Margosiak, S.; Almassy, R.;
Lu, J.; Averill, A.; Yager, K. M.; Chu, S. Structure-based design,
synthesis, and study of pyrazolo[1,5-a][1,3,5]triazine derivatives as
potent inhibitors of protein kinase CK2. Bioorg. Med. Chem. Lett. 2007,
17, 4191−4195.
ASSOCIATED CONTENT
■
S
* Supporting Information
Representative experimental procedures for synthesis of
analogues, biochemical and cellular assays, and X-ray structure
determination. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) The PDB deposition code for the cocrystal structure is 3U4U.
(18) Williamson, D. S.; Parratt, M. J.; Bower, J. F.; Moore, J. D.;
Richardson, C. M.; Dokurno, P.; Cansfield, A. D.; Francis, G. L.;
Hebdon, R. J.; Howes, R.; Jackson, P. S.; Lockie, A. M.; Murray, J. B.;
Nunns, C. L.; Powles, J.; Robertson, A.; Surgenor, A. E.; Torrance, C.
J. Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors
of human cyclin-dependent kinase 2. Bioorg. Med. Chem. Lett. 2005, 15,
863−867.
AUTHOR INFORMATION
Corresponding Author
*Telephone: 781-839-3900. E-mail: james.dowling@
astrazeneca.com.
■
Notes
The authors declare no competing financial interest.
(19) Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.;
Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.;
Edeen, P. T.; Faraoni, R.; Floyd, M.; Hunt, J. P.; Lockhart, D. J.;
Milanov, Z. V.; Morrison, M. J.; Pallares, G.; Patel, H. K.; Pritchard, S.;
Wodicka, L. M.; Zarrinkar, P. P. A quantitative analysis of kinase
inhibitor selectivity. Nat. Biotechnol. 2008, 26, 127−132.
(20) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. New diphosphine
ligands based on heterocyclic aromatics inducing very high
regioselectivity in rhodium-catalyzed hydroformylation: effect of the
bite angle. Organometallics 1995, 14, 3081−3089.
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