Discovery of potent, selective and orally bioavailable imidazo[1,5-a] pyrazine derived ACK1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.12.042

This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and

Full text of DOI:10.1016/j.bmcl.2012.12.042

Bioorganic & Medicinal Chemistry Letters 23 (2013) 979–984
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of potent, selective and orally bioavailable
imidazo[1,5-a]pyrazine derived ACK1 inhibitors
⇑
Meizhong Jin , Jing Wang, Andrew Kleinberg, Mridula Kadalbajoo, Kam W. Siu, Andrew Cooke,
Mark A. Bittner, Yan Yao, April Thelemann, Qunsheng Ji, Shripad Bhagwat, Kristen M. Mulvihill,
Josef A. Rechka, Jonathan A. Pachter, Andrew P. Crew, David Epstein, Mark J. Mulvihill
OSI Pharmaceuticals, LLC, A Wholly-Owned Subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine
derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent explo-
ration of structure–activity relationships and optimization of drug metabolism and pharmacokinetic
properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 October 2012
Revised 12 December 2012
Accepted 13 December 2012
Available online 21 December 2012
Keywords:
Activated Cdc42-associated kinase (ACK1)
Inhibitors
Structure–activity relationships (SAR)
Imidazo[1,5-a]pyrazine
Cancer
Activated Cdc42-associated kinase (ACK1) is a non-receptor
tyrosine kinase originally identified by virtue of its binding to
GTP-bound small GTPase Cdc42.1 It is ubiquitously expressed and
is activated by multiple extracellular growth factors such as EGF,
PDGF, and TGFb. Upon activation, ACK1 mediates a signaling cas-
cade by directly interacting with and phosphorylating downstream
effectors.2 Considerable attention has been paid to the biological
function of ACK1 in recent years especially to its involvement in
cancer.3 For example, gene amplification and over-expression of
ACK1 were found in multiple cancers including lung, ovarian and
prostate cancers and were associated with poor prognosis and
metastatic phenotypes.4 Activated ACK1 has been shown to phos-
phorylate and activate androgen receptor function and to promote
the progression of prostate cancer.5 More recently, activated ACK1
was found to phosphorylate and promote the activation of Akt, a
protein kinase that plays a central role in growth, proliferation
and cell survival in various cancers.6 Taken together, these litera-
ture data suggest that ACK1 is a potential target for cancer treat-
ment. Moreover, a potent and selective small molecule ACK1
inhibitor will provide a valuable tool to help to further probe the
role of ACK1 in cancer.
example from this series with a reported ACK1 cellular mechanistic
IC50 value of 20 nM (Fig. 1). A series of 5,6-biarylfuro[2,3-d]pyrim-
idines and bioisosteric 2,3-diarylfuro[2,3-b]pyridines and 5,6-bia-
rylpyrrolo[2,3-d]pyrimidines have also been reported as potent
ACK1 inhibitors.8 For example, compound 2a inhibits ACK1 in a
cellular mechanistic assay with an IC50 value of 10 nM. Another
compound from this class, AIM-100 (compound 2b, Fig. 1) moder-
ately inhibits ACK1 with a cellular mechanistic IC50 value of
0.62 lM, suppressing both ACK1 Tyr284- and androgen receptor
Tyr267-phosphorylations in vitro.8d,9 Unfortunately, these dis-
closed compounds suffered poor oral pharmacokinetic (PK) proper-
ties due to metabolic instability which prevented them from being
utilized further in the in vivo setting. Herein we report our drug
discovery effort around small molecule ATP competitive ACK1
inhibitors. More specifically, the initial discovery, optimization
and in vitro and in vivo characterization of a series of imi-
dazo[1,5-a]pyrazine-derived inhibitors of ACK1 which possessed
favorable drug-like properties including potency, selectivity and
orally bioavailability.
Our initial approach to identify hits was two-pronged and in-
cluded a high-throughput screening (HTS) campaign of the OSI
compound library as well as a virtual screening (VS) campaign, uti-
lizing a publically available crystal structure of ACK1 (PDB code:
1U4D). A tolerance for protein flexibility was incorporated into
the virtual screening design with the hope of identifying hits which
would require diverse protein conformations for binding, since
such potential hits might be rejected if a rigid protein structure
A series of pyrazolo[3,4-d]pyrimidines has been previously
disclosed as ACK1 inhibitors.7 Compound 1 is a representative
⇑
Corresponding author.
E-mail address: Meizhong.jin@astellas.com (M. Jin).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.12.042

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M. Jin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 979–984
OMe
S
S
N
O
N
F
N
HN
HN
N
N
H
O
N
N
N
O
N
N
H
N
N
O
H
N
2b (AIM-100)
1
2a
Figure 1. Representative ACK1 inhibitors disclosed in literature.
from the initial static view of the crystal structure (PDB code:
1U4D). The cyclobutyl moiety, termed the southern domain
(SoD), emanating from C3 of the core, extends past the glycine rich
P-loop and towards the solvent exposed region of the protein.
To further explore and build SAR around compound 3, we first
sought to analog around the NoD moiety and specifically ring A
while keeping the rest of the molecule constant (Table 1). Various
substitutions encompassing different sizes and electronic proper-
ties were walked around the ring. While C2-F (compound 4) and
C3-F (compound 7) substitutions offered a slight increase in po-
tency, all other substitutions resulted in a loss of potency. In the
C4 position of ring A, substitution consistently resulted in a loss
of potency. This observation was in agreement with modeling pre-
dictions which suggested that phenyl as ring A optimally fit into
this hydrophobic pocket as there is not enough additional space
available to accommodate further substituents. Pyridyl variant 13
was also evaluated and found to be inferior to the phenyl group
in terms of ACK1 potency, most likely due to an unfavorable
desolvation penalty introduced by the pyridine nitrogen atom.
Replacement of ring A with alkyl groups such as methyl, isopropyl
and cyclohexyl groups abolished potency (data not shown), sug-
gesting phenyl is an optimal pharmacophoric element at this
position.
We next sought to explore the SAR around the proximal phenyl
ring (ring B) of the NoD moiety. While using phenyl as a template
for ring B, modeling studies suggested that a hydrogen bond accep-
tor substituted off the C20 position could form a hydrogen bond
interaction with the side chain hydroxyl group of the gatekeeper
Thr205 and thus may improve potency. As shown in Table 2, while
both C20-OMe (compound 14, Fig. 4a) and C20-F (compound 15)
substitutions increased potency over 3, C20-Cl (compound 16)
and C20-Me (compound 17) substitutions decreased potency. These
results, when taken together, helped to further validate the model.
Other hydrogen bond acceptor moieties evaluated at this position
such as amides (compounds 18–19) generally abolished potency
Ring A
NoD linker
O
Northern domain (NoD)
Ring B
NH2
1
N
Core
N
N
3
5
South domain (SoD)
3
Figure 2. Imidazo[1,5-a]pyrazine hit, compound 3, discovered from ACK1 virtual
screening.
was used. In order to confirm the potency of prioritized virtual
screening hits, an Alpha-screen assay (ATP concentration of
100
(MW = 356) imidazo[1,5-a]pyrazine-derived compound 3 (Fig. 2)
emerged as a potent hit (IC50 = 0.19 M). Detailed computational
l
M)10 was implemented where the low molecular weight
l
studies were then performed on compound 3, with some of the
major modeled interactions between this compound and ACK1
highlighted in Figure 3. The C8-amino group and N7 of the imi-
dazo[1,5-a]pyrazine core of the compound form two hydrogen
bonds with the hinge backbone amides. The 4-phenoxyphenyl
moiety, termed the northern domain (NoD), substituted from the
C1 position of the core, passes through a channel occupied by gate-
keeper Thr205, with the ring A moiety further extending into a
lipophilic pocket primarily formed by Val178 and Met181 of the
a
C-helix as well as Leu192, Met203, Thr205 and Phe271 (F of the
DFG loop). Furthermore, modeling studies suggested a protein con-
formational change associated with this proposed binding mode,
since the accommodation of ring A of 3 required an enlargement
of the back pocket from its original size which was not evident
Figure 3. Modeled interactions of compound 3 with ACK1. (a) Section view of ACK1 surface based on the initial crystal structure (PDB code: 1U4D) after removing the original
ligand and manually placing compound 3 without energy minimization. (b) Section view of ACK1 surface after energy minimization of the complex with compound 3 where
the enlargement of the back pocket is evident. (c) Critical interactions in the minimized modeling structure.

M. Jin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 979–984
981
Table 3
Table 1
Quantum chemistry calculation of the total energy DDEa of compounds 14 and 20
with respect to 3
SAR of NoD moiety—ring A
3
2
b
c
NH2
Compd
DDGs
DDEc
DDEid
DD
E
ACK1 biochem IC50 (lM)
NoD
4
NoD =
Ring A
O
O
R1
3
14
20
0
0.38
9.13
0
0.78
2.53
0
0
0.19
0.048
>10
N
N
N
N
ꢁ3.72
ꢁ2.56
ꢁ5.62
6.04
a
DDE = DDGs + DDEc
DDGs: The difference of the solvation free energies of compounds 14 and 20
+
DDEi.
b
3-12
13
compared to that of compound 3.
c
DDEc: The difference of energy cost associated with conformational changes of
compounds 14 and 20 before and after binding compare to that of compound 3.
DDEi: The difference of interaction energies of compounds 14 and 20 compared
to that of compound 3.
d
a
Compd
R1
ACK1 biochem IC50 (lM)
3
4
5
6
7
8
9
10
11
12
13
H
2-F
0.19
0.10
0.24
0.74
0.11
0.24
3.19
5.46
0.90
1.87
1.90
2-Me
2-Cl
3-F
3-Me
3-Cl
4-F
as this was most likely caused by steric clashes with the protein
due to limited binding space in this region. Interestingly, pyridone
analog 20 was found to be inactive although there were no steric
issues in binding as suggested by modeling, and the pyridone car-
bonyl is a strong hydrogen bond acceptor based on its pKBHX va-
lue.11 To further clarify this apparent discrepancy, we performed
quantum chemistry calculations on binding interactions of com-
pounds 3, 14 and 20.12 As shown in Table 3, compound 20 indeed
formed a stronger hydrogen bond interaction with Thr205 com-
pared to 14 as indicated by a more favorable interaction energy
gain (DDEi) but suffered a much greater energy loss due to an in-
creased desolvation penalty (DDGs) and adverse conformational
changes (DDEc). As a result, compound 20 had a overall energeti-
cally unfavorable interaction (DDE) which rendered it inactive.
In terms of the ring B C50 position, while C50-F (compound 21)
was tolerated, C50-Me (compound 22) and C50-Cl (compound 23)
substitutions resulted in a loss in potency. However, the C50-OMe
substitution (compound 24) resulted in a ꢀ3-fold increase in po-
tency compared to 3. Modeling suggested a pseudo hydrogen bond
interaction between the C50-OMe group and the carbonyl of Gly269
(Table 3, Fig. 4b).13 A C50-OEt substitution (compound 25) resulted
in a decrease in potency, speculated to be due to the bulkier ethoxy
group and the ensuing desolvation of Asn257, Arg256 and Gly269.
The SAR around the NoD linker moiety which connects rings A
and B was also explored (Table 4). This effort primarily focused on
one-atom-length tethers, due to the concern that an extended
linker would simply push ring A into a steric clash with the protein,
as suggested by modeling and SAR previously established and
highlighted in Table 1. Various bioisosteric replacements to the
oxygen linker in compound 3 were generally tolerated with the
observation of less than threefold loss of potency (compounds
4-Me
4-Cl
a
Throughout this Letter, all IC50 values are an average of at least two values.
Table 2
SAR of NoD moiety—ring B
NH2
NoD
NoD =
O
O
2'
N
N
N
N
R2
Ring B
5'
3, 14-19, 21-25
20
Compd
R2
H
ACK1 biochem IC50 (lM)
3
0.19
0.048
0.088
1.69
6.28
>10
14
15
16
17
18
19
20
21
22
23
24
25
20-OMe
20-F
20-Cl
20-Me
20-NHCOMe
20-CONH2
>10
>10
50-F
0.22
0.37
1.06
0.075
0.47
50-Me
50-Cl
50-OMe
50-OEt
Figure 4. Modeled interactions of compounds 14 and 24 with ACK1. (a). The C20-OMe group of 14 forms a hydrogen bond with Thr205 (MeO. . .OH distance: 2.77 Å); (b) the
C50-OMe group of 24 forms a pseudo hydrogen bond with Gly269 carbonyl (C(H2)–H. . .O@C distance: 3.60 Å).

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M. Jin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 979–984
Table 4
SAR of NoD linker moiety
interactions with Lys158. Several 5,6-cyclized systems (com-
pounds 31, 32) suffered significant losses of potency, speculated
to be due to the inability to adopt the required bioactive conforma-
tion possessed by 3 (Fig. 3). Subsequently, we successfully ob-
tained a co-crystal structure of compound 33, a close analog of 3,
with the ACK1 kinase domain (PDB code: 4ID7). The interactions
revealed in this co-crystal structure essentially confirmed the bind-
ing mode proposed by modeling, including the predicted enlarge-
ment of the back pocket to accommodate ring A of the NoD
moiety (Fig. 5).
S
Linker
NH2
NoD
X
N
N
NoD =
N
N
N
3, 25-30
31
32
While expanding the SAR around the NoD moiety, we con-
ducted a mouse PK study on compound 3 to benchmark its DMPK
properties. As summarized in Table 5, at an oral dose of 20 mg/kg,
compound 3 displayed good oral bioavailability (50%) with a mod-
Compd
X
ACK1 biochem IC50 (lM)
3
O
S
NH
CH2
C@O
CHOH
C(OH)Me
0.19
0.33
0.38
0.57
0.087
0.28
0.090
3.35
4.09
25
26
27
28
29
30
31
32
erate exposure as indicated by a plasma Cmax of 0.9 lM. The intra-
venous clearance was higher than mouse liver blood flow (ꢀ90 mL/
min/kg), as was predicted by the high mouse hepatic extraction ra-
tio (mouse ER = 0.89) observed upon in vitro incubation in micro-
somes. Furthermore, two significant M + 16 metabolites were
detected in both oral (ꢀ65% of parent AUC) and intravenous plas-
ma samples (ꢀ20% of parent AUC). Mass fragmentation analysis
suggested that both metabolites were produced from hydroxyl-
ation of the cyclobutyl southern domain moiety (SoD) via a
phase-I mechanism. Compound 33 was synthesized and confirmed
as one of the metabolites based on LC–MS/MS (the other
25–27). Several variants of the carbon based linker such as
carbonyl (compound 28) and alcohols (compound 29, 30) showed
increased potency over compound 27. This was rationalized
through the model where these linkers formed hydrogen bond
Figure 5. Co-crystal structure of ACK1 and 33 (PDB code: 4ID7) along with a side-by-side comparison with the predicted modeling structure. (a) Section view of ACK1 surface
in complex with 33 based on the co-crystal structure. (b) Critical interactions between 33 and ACK1 in the co-crystal structure. (c) Critical interactions between 3 and ACK1 in
the modeling structure.
Table 5
Key mouse PK parameters of compounds 3, 34
O
O
O
NH2
NH2
NH2
in vivo metabolism
N
N
N
N
N
N
N
N
N
OH
OH
3
33
34
Compd
Mouse oral PK (20 mg/kg)
AUC (ng h/mL)
Mouse iv PK (2 mg/kg)
CL (mL/min/kg)
Cmax
(l
M)
t1/2 (h)
F%
Vss (L/kg)
3
34
0.9
11.2
1236
4680
5.5
4.9
50
87
9.0
1.7
135
62

M. Jin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 979–984
983
metabolite was speculated to be the trans-isomer). Compound 34
was subsequently synthesized where the C3 position of cyclobutyl
moiety was fully substituted in order to block this primary route of
metabolism. To our satisfaction, compound 34 maintained similar
potency (biochem IC50 = 0.16
l
M) to that of compound 3 while
showing significantly improved in vitro microsomal stability
(mouse ER = 0.60). A mouse PK study with compound 34 showed
significantly improved oral exposure, decreased intravenous
Table 6
Combination of preferred SoD and NoD pharmacophores
NH2
NoD
X
N
N
N
R2a
R2b
NoD =
HO
Compd
R2a
R2b
X
ACK1 biochem IC50
(lM)
ACK1 cell mech. IC50
(
lM)
E.R. (m/h)
35
36
37
38
39
40
41
42
F
H
H
F
H
H
H
F
C@O
C@O
C@O
CH2
CF2
C(OH)Me
O
O
0.14
0.11
0.088
0.23
0.45
0.22
0.13
0.11
0.030
0.029
0.028
0.058
0.17
0.084
0.051
0.035
0.71/0.93
0.50/0.91
0.86/0.86
0.77/0.81
0.65/0.63
0.52/0.57
0.53/0.77
0.55/0.53
OMe
H
H
H
H
F
H
OMe
Table 7
Key mouse PK parameters of compounds 39, 40 and 42
Compd
Mouse oral PK (20 mg/kg)
Mouse iv PK (2 mg/kg)
CL (mL/min/kg)
Cmax
(
lM)
AUC (ng h/mL)
t1/2 (h)
F%
Vss (L/kg)
39
40
42
5.0
4.6
5.9
8544
3943
8484
4.3
2.6
3.8
160
105
98
1.7
3.3
1.8
63
89
39
Table 8
Physicochemical and ADMET properties of compound 42
CYP inhibition
IC50
(l
M)
Miscellaneous physicochemical and ADMET properties
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP3A4
>20
>20
16.3
>20
>20
MW/AlogP/PSA
416/3.16/94.9 (Å)
591 (pH 7.4)
280 (pH 5.0)
PAMPA (10ꢁ6 cm/s)
Aq solubility
>100
>15
lM (pH 7.4)
hERG (IC50
)
l
M
Ph
O
O
Ph
O
OH
O
Ph
O
O
a
b
B
O
O
O
Br
Cl
Br
N
NH2
45
44
43
e
N
N
N
Cl
NH2
Br
Br
Br
N
c
N
d
N
N
N
N
HO
N
N
42
47
HO
48
HO
O
46
Scheme 1. Reagents and conditions: (a) PhB(OH)2, Cu(OAc)2, Et3N, DCM, rt, 42%; (b) PdCl2(dppf), KOAc, bis(pinacolato)diboron, dioxane, 80 °C, 75%; (c) MeMgCl, THF, ꢁ78 °C,
70%; (d) NH3 in water (35%), 2-butanol, 90 °C, 95%; (e) PdCl2(dppf), K2CO3, dioxane–water (4:1, v:v), 95 °C, 68%.

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M. Jin et al. / Bioorg. Med. Chem. Lett. 23 (2013) 979–984
clearance with no significant metabolites detected in plasma. Sub-
sequently, a systematic SAR exploration around the SoD (data not
shown) revealed that the methyl cyclobutanol moiety shown in
compound 34 was a preferred pharmacophoric element for this re-
gion of the molecule.
demonstrated good in vivo PK properties, which makes it a valu-
able compound to probe the in vivo biology of ACK1.
Acknowledgments
After extensive SAR exploration on key pharmacophoric ele-
ments as described above, preferred SoD and NoD groups were
merged, with a representative list of compounds highlighted in
Table 6. Compounds with carbonyl and methylene NoD linkers
(35–38) gave both good biochemical and cellular mechanistic
potencies14 but less optimal DMPK properties as indicated by rela-
tively high extraction ratios (low microsomal stability) in both
mouse and human liver microsomes. Compound 39, with a gem-
difluoromethylene linker, showed improved microsomal stability,
however, it suffered a moderate potency loss. Compound 40 with
the tertiary alcohol linker motif and compounds 41–42 with an
oxygen linker demonstrated both good potency and good micro-
somal stability. Key compounds were progressed to mouse PK
studies and the results are summarized in Table 7. All three com-
pounds tested had good oral exposures and were highly bioavail-
able with moderate rates of clearance. It should be noted that in
these studies, compound 40 was evaluated as a racemic mixture.
The enantiomers were later separated by chiral supercritical fluid
chromatography (SFC) and subjected to mouse PK studies. Both
enantiomers showed similar PK profiles to 40, with no racemiza-
tion detected in vivo by chiral HPLC analysis of the plasma
samples.
The authors gratefully acknowledge Dr. Yingjie Li and Ms. Vio-
rica M. Lazarescu for analytical support; Mr. Paul Maresca, Mr. Pete
Meyn and the Leads Discovery Group for conducting in vitro AD-
MET studies; The authors also gratefully acknowledge Proteros
Biostructures GmbH for collaboration on ACK1 co-crystallization
effort.
References and notes
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To understand the kinase selectivity profile of this series, com-
pound 42, as a representative analog from this series, was profiled
against 216 purified protein kinases representing the tyrosine and
serine/threonine kinase families using an in-house Caliper EZ
Reader mobility shift assay. Assays were conducted with the con-
centration of ATP at Km for each individual kinase with compound
42 at a concentration of 1.0 lM. Among 216 kinase screened, com-
pound 42 showed ꢀ100% inhibition of ACK1 and >80% inhibition of
12 other kinases. Of the 12 off-target kinases, none were consid-
ered major cell growth drivers such as receptor tyrosine kinases
or cell-cycle regulating kinases.15 The selectivity was further con-
firmed by KINOMscan profiling against an even larger panel of
451 kinases, where compound 42 showed a selectivity score of
S(10) = 0.08, which represents a relatively high degree of selectiv-
ity.16 Compound 42 possesses favorable drug-like properties as
indicated by its physicochemical and ADMET properties, as sum-
marized in Table 8. A convergent synthesis of compound 42 is illus-
trated in Scheme 1. Phenol 43 was converted to di-phenyl ether 44
though a Cu(II) mediated Chan–Lam coupling,17 the subsequent
palladium catalyzed borylation of 44 afforded the desired boronate
45. The key imidazo[1,5-a]pyrazine intermediate 46 was treated
with methyl Grignard reagent MeMgCl followed by an ammonoly-
sis to give compound 48, which then underwent a Suzuki coupling
with boronate 45 to provide compound 42.10
9. Mahajan, K.; Challa, S.; Coppola, D.; Lawrence, H.; Luo, Y.; Gevariya, H.; Zhu, W.;
Chen, Y.; Lawrence, N.; Mahajan, N. P. Prostate 2010, 70, 1274.
10. Crew, A. P.; Jin, M.; Kadalbajoo, M.; Kleinberg, A.; Mulvihill, M. J.; Wang, J. US
20090286768. Detailed biochemical assay and cellular mechanistic assay
protocols, as well as synthesis of key intermediates and final compounds are
described therein.
11. Laurence, C.; Brameld, K. A.; Graton, J.; Le Questel, J. Y.; Renault, E. J. Med. Chem.
2009, 52, 4073.
12. The calculations were performed with Jaguar program version 6.5 licensed
from Schrodinger, Inc., Poland, OR. The B3LYP functional and 6-31G⁄⁄ basis set
were used. To obtain the free state conformation of
a compound, the
geometrical optimizations with multiple starting points were performed.
13. Bissantz, C.; Kuhn, B.; Stahl, M. J. Med. Chem. 2010, 53, 5061.
14. The ACK1 biochemical potencies and cellular mechanistic potencies for this
series of compounds are well correlated (R2 = 0.76).
In summary, a series of imidazo[1,5-a]pyrazine derived ACK1
inhibitors was identified through a combination of structure-based
drug design and empirical medicinal chemistry efforts. Efforts
originated from virtual screening hit 3, where SAR exploration
and DMPK optimizations eventually led to compound 42, a
potent and selective ACK1 inhibitor with favorable in vitro physi-
cochemical and ADMET properties. Furthermore, compound 42
15. Compound 42 showed >80% inhibition to following kinases (other than ACK1)
when screened at 1.0
LYNB, SRC, SRMS, TEC, TXK, YES.
16. Selectivity score is quantitative measure of compound selectivity. It is
lM against 216 kinases: BLK, FGR, FRK, FYN, HCK, LCK,
a
calculated as such: selectivity score = (number of hits)/(number of assays).
S(10) is calculated using 10% control as a potency threshold: S(10) = (number of
kinases with % control <10)/(number of kinases tested). Further information
regarding to selectivity score is available at http://www.kinomescan.com.
17. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.