Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K

Article abstract of DOI:10.1016/j.bmcl.2013.06.010

PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN p

Full text of DOI:10.1016/j.bmcl.2013.06.010

Accepted Manuscript
Structure Guided Optimization of a Fragment Hit to Imidazopyridine Inhibitors
of PI3K
Sabina Pecchi, Zhi-Jie Ni, Wooseok Han, Aaron Smith, Jiong Lan, Matthew
Burger, Hanne Merritt, Marion Wiesmann, John Chan, Susan Kaufman, Mark
S. Knapp, Johanna Janssen, Kay Huh, Charles F. Voliva
PII:
S0960-894X(13)00719-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.06.010
BMCL 20574
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 April 2013
30 May 2013
3 June 2013
Please cite this article as: Pecchi, S., Ni, Z-J., Han, W., Smith, A., Lan, J., Burger, M., Merritt, H., Wiesmann, M.,
Chan, J., Kaufman, S., Knapp, M.S., Janssen, J., Huh, K., Voliva, C.F., Structure Guided Optimization of a Fragment
Hit to Imidazopyridine Inhibitors of PI3K, Bioorganic & Medicinal Chemistry Letters (2013), doi: http://dx.doi.org/
10.1016/j.bmcl.2013.06.010
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Structure Guided Optimization of a Fragment Hit to
Imidazopyridine Inhibitors of PI3K
Sabina Pecchia, Zhi-Jie Nia, Wooseok Hana*, Aaron Smitha, Jiong Lana, Matthew
Burgera, Hanne Merrittb, Marion Wiesmannc, John Chanb, Susan Kaufmanb, Mark S.
Knappa, Johanna Janssena, Kay Huha, and Charles F. Volivab
aGlobal Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for Biomedical Research,
b
c
Emeryville, CA, U.S.A., Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA, U.S.A., Oncology DA,
Novartis Institutes for Biomedical Research, Basel, Switzerland
Received Month XX, 2013; Accepted Month XX, 2013
Abstract—PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and
differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3K overexpression, gene amplification, mutations
and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we
describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early
chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl
imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.
©2000 Elsevier Science Ltd. All rights reserved.
* Corresponding author. Tel.: +1(510) 923-2848; Fax: +1(510) 923-3360; E-mail: wooseok.han@novartis.com

Phosphatidylinositol 3-kinases (PI3Ks) are a family of
lipid and serine/threonine kinases involved in a
diverse set of cellular functions.1 PI3Ks can be
categorized in class I, II or III, depending on their
subunit structure, regulation and substrate selectivity.2
Class IA PI3Ks are heterodimers composed of a
against the isoform and less potent against the  and
 isoforms, PI4K and VPS34.21 We were therefore
intrigued by the opportunity to explore this selectivity
potential.
catalytic p110 subunit (,
 and isoforms)
constitutively associated with a regulatory subunit that
can be p85, p55, p50, p85 or p55. The Class IB
has one family member, a heterodimer composed of a
catalytic p110 subunit associated with one of two
regulatory subunits, p101 or p84. Class IA PI3Ks are
activated by tyrosine kinases while Class IB is
activated by G protein-coupled receptors, therefore
linking upstream receptors with downstream cellular
activities including cell growth, proliferation, survival,
chemotaxis, cellular trafficking, membrane ruffling
and glucose homeostasis,1 motility, metabolism,
inflammatory and allergic responses, transcription and
translation.2,3 PI3Ks catalyze the transfer of phosphate
to the D-3’ position of inositol lipids to produce
phosphoinositol-3-phosphate (PIP), phosphoinositol-
3,4-diphosphate (PIP2) and phosphoinositol-3,4,5-
triphosphate (PIP3), second messengers in numerous
signaling cascades.4 In many cases, PIP2 and PIP3
recruit AKT to the plasma membrane where it acts as
a nodal point for many intracellular signaling
pathways important for growth and survival.5,6
Aberrant regulation of PI3K, which often increases
survival through AKT activation, is one of the most
prevalent events in human cancer7 and can occur at
multiple levels.8,9 In particular, p110 pathway
deregulation has been demonstrated in ovarian, breast,
colon and brain cancers.10,11 These observations
support the inhibition of Class I PI3 kinases as a
potential treatment for a variety of tumor types and
other proliferative diseases,12,13 hence the interest
during the last ten years in generating suitable
molecules to test this hypothesis in the
clinic.14,15,16,17,18
Figure 1. Clinical candidate 1 (NVP-BKM120) and benzothiazole
fragment hit 2
In silico profiling of 2 (PSA = 96, cLogP = 2.0,
LogD7.4 = 1.5, 1 HBD, 3 HBA, good predicted passive
permeability) did not show any significant alerts. One
significant advantage in the follow up was the
availability of a co-crystal structure of 2 in
p110obtained shortly after hit triaging.
Figure 2. Model of compound 2 and NVP-BKM120 (1) in p110.
Fig. 2 shows an overlay of compound 2 with NVP-
BKM120 (1, Fig. 1), the lead compound from the 2-
morpholinopyrimidine series,20 in a homology model
of p110. This model was generated based on the co-
crystal structures of both compounds in p110 It is
worth noting that the 2-acetamidobenzothiazole
scaffold provides one additional contact with the hinge
binding domain of the ATP binding site in comparison
to the morpholine. The acetamide NH acts as a H
bond donor and the benzothiazole N acts as a H bond
In the course of our efforts to identify a backup series
for our 2-morpholino pyrimidines front runners19 and
NVP-BKM120 (1, Fig. 1),20 we conducted a second
HTS campaign on an expanded compound collection
and fragment library. Through this effort, several hits
were identified and compound 2 (a fragment with MW
= 250.2, Fig. 1) was selected for follow up.
Compound
2
had reasonable potency against
PI3Kandgood ligand efficiency (IC50 = 2.2 M, LE
= 0.47). It appeared to be approximately equipotent

acceptor with VAL851 backbone carbonyl and NH,
respectively. The third hydrogen bond interaction is
provided by the carbonyl of the ester substituent in the
carcinoma cell line was 0.5 M). Aminopyridine 6
maintained high Ligand Efficiency (LE = 0.5) and was
almost 35-fold more potent than 2. Consequently,
mechanism modulation was enhanced to a level
sufficient to observe a signal in our functional assay
(inhibition of cell proliferation EC50 = 2.9 M).
Interestingly, aminopyrimidine 7 was comparable to 6,
indicating that the SAR was not tracking with the earlier
6-position with the OH of TYR836.
The
benzothiazole spans two key regions of the active site
(hinge domain and catalytic region) more efficiently
than the 2-morpholinopyrimidine series, where the
central pyrimidine ring has mainly a scaffolding
function. The ester interaction is likely inefficient, but
the 6-position of the benzothiazole provides a good
vector for growth in the direction of the “affinity
pocket”, accessing the same area of the binding site as
the one occupied by the aminopyridine in the 2-
2-morpholinopyrimidine
series,
where
6-
aminopyrimidine analogs were 50 to 100-fold more
potent than the pyridines.19 Furthermore, a CF3 group in
the 4’-position of 8, the preferred position for
substitution in the 2-morpholinopyrimidine series,19,20
morpholinopyrimidine series.
This indicated the
was not tolerated.
On the other hand, various
potential for hybridizing the two chemotypes.
substituents were tolerated in the 3’-position (e.g. 9-11).
The 3’-CF3 analog 9 was the most potent with almost 10-
fold biochemical potency improvement compared to 6
and with a 2- and 7-fold improvement in mechanism
modulation and inhibition of cell proliferation,
respectively. It is worth noting, however, that neither LE
nor LLE (0.47 and 4.9) were improved for 9 compared to
6 (LLE = 4.8).
Thus, this hybridization approach led to the quick
identification of novel, potent PI3K inhibitors. Potency
against the other isoforms was also improved, and the
series was not as selective as initially observed for
compound 2 (e.g. PI3K IC50 was 0.030 M for 6) but
was still an interesting starting point for pan Class I PI3K
We therefore proceeded to synthesize a series of
benzothiazoles having 6-membered rings at the 6-
position. The analogs were easily obtained from
commercially
available
2-amino-6-bromo
benzothiazole 3 by acetylation and Suzuki coupling
with various heterocyclic boronic esters, either
commercially available or synthesized as previously
described23 (Scheme 1).
inhibitors.
Both compounds 6 and 9 had good
microsomal stability and permeability, with low efflux
potential in the Caco-2 assay.24 The compounds were
advanced to rat PK (Table 5) where they demonstrated
oral exposure. However, based on our understanding of
PK/PD efficacy relationship in this series, this exposure
would not have sufficed for inhibiting tumor growth in
our in vivo mouse xenograft model. In addition, low
solubility (4.2 and 1.5 M) and CYP450 inhibition (IC50
for 3A4 = 0.05 and 0.8 M) were significant issues. To
address solubility, we introduced basic amines in the 2-
Scheme 1. Synthesis of 6-heteroaryl substituted 2-acetamido
benzothiazoles. Reagents and conditions: (a) Ac2O, THF, r.t.; (b) 2M
.
Na2CO3, Pd(dppf)Cl2 CH2Cl2, DME, microwave, 115˚C, 10 min.
Some of the results obtained are summarized in Table 1.
pAKTser473
IC50
pAKTser473
IC50
PI3K
IC50
Prol.
EC50
PI3K
IC50
Prol. EC50
#
2
R
#
8
R
position (solvent exposed).
Some of the results are
F
shown in Table 2. We observed potency loss, but to a
lesser extent when more than one carbon tether was
introduced on the amide (compare 6 with 13), and up to
80-fold improvement in solubility (6 vs. 14). Tracking
with the 2-acetamido series, the 3’-CF3 aminopyridines
were more potent than the unsubstituted aminopyridines
(10 to 20-fold, 14 vs. 13). Morpholine was also used as
solubilizing group (compound 15), but was less effective.
Due to lower efficiency (no potency improvement
accompanied the increase in MW) and increased efflux
potential (e.g. Caco-2 for compound 11 = A-B 6.7, B-A
18, B/A 2.7), this series was promptly abandoned.
O
C
CH3
F
F
CH3
CH3
CH3
2.2
ND
ND
9.7
2.9
1.3
2.0
ND
ND
O
H3
H2
N
N
N
N
F
CH3
F
F
5
6
7
9
0.11
0.50
0.14
0.19
0.0079
0.036
0.033
0.08
0.30
0.11
0.41
2.5
N
H2
N
CH3
H3C
10
11
0.063
0.054
H2
N
N
N
H2N
CH3
O
H3C
CH3
N
0.67
H2
N
N
H2
N
Table 1. Position 6- SAR in the benzothiazole series. IC50 and EC50 in
M. Cell line: A2780 ovarian carcinoma.
Replacement of the ester in compound 2 with a 3-pyridyl
(5) gave a 20-fold potency improvement in the
biochemical assay, and showed some pathway
modulation (IC50 for the inhibition of AKT
phosphorylation on SER473 in the A2780 ovarian

pAKTser473
IC50
>25 M against CYP450 3A4, 1A2, 2D6, 2C9, and
2C19).
#
6
R1
H
R2
PI3K IC50
0.063
0.0079
1.2
Prol. EC50 Solubility
The synthesis of compound 17 is shown in Scheme 2.25
Tosylation of 2-amino-4-iodopyridine and N-alkylation
with iodo acetamide led to intermediate 24 which
cyclized upon treatment with TFAA. The resulting
imidazopyridine 2-trifluoroacetamide was deprotected
with potassium carbonate and the 2-amino group was
acetylated, to give 5-I derivative 25. Compound 25 was
CH3
CH3
0.14
0.08
ND
2.9
0.41
ND
5.9
4.2
1.5
7.1
28
9
CF3
H
CH2
N
12
13
14
15
(CH2)3
(CH2)3
(CH2)3
N
H
0.26
0.36
0.11
0.15
N
N
CF3
CF3
0.014
0.025
1.8
56
then
coupled
with
5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine
26 under Suzuki conditions23 to give the desired
compound 17.
O
4.1
8.3
Table 2. Variations on the acetamide for solubility improvement. IC50,
EC50 and solubility (PBS) in M (pH 7.4). Cell line: A2780 ovarian
carcinoma.
Biochemical Profile (IC50, M)
PI3K
PI3KE542K PI3KH1047R
PI3K
A strategy focused on modifications of the core structure
was then undertaken. In particular, a series of 5,6- and
6,6-fused heterocycles were explored as benzothiazole
replacements and some results are shown in Table 3.
0.0036
PI3K
0.27
0.0059
PI3K
0.1
0.012
PI4K
2.35
0.0082
VPS34
1.8
Cellular Profile (EC50, M)
pAKTS473
pAKTT308
<0.041
<0.041
ND
Cell line
Proliferation
A2780
U87MG
T47D
0.079
0.050
0.034
1.1
2.0
1.3
pAKTser473
#
Core
PI3K IC50
Prol. EC50 cLogp Solubility
IC50
N
S
Table 4. In vitro profile of compound 17.
CH3
CH3
9
0.008
0.08
0.41
0.42
3.1
1.7
1.5
1.0
H3C
H3C
The co-crystal structure of 17 with p110 gave further
insights in the binding mode (Fig. 3). The nitrogen atom
in the imidazopyridine core forms a hydrogen bond with
VAL882 backbone NH, and the 2-acetamide NH forms
an interaction with VAL882 backbone carbonyl, as
expected. The endocyclic N of the 5-aminopyridine
substituent functions as H bond acceptor with TYR867
OH and the NH2 donates to ASP964. Compared to the
morpholino pyrimidine scaffold (Fig. 2),19 this
substituent is not buried as deep in the catalytic region,
but the CF3 group fits in the same hydrophobic pocket,
accessing it through a different vector. Substituents in
4’-position are not tolerated because this position does
not provide the right trajectory to the same hydrophobic
N
16
0.002
0.020
N
N
N
N
CH3
CH3
17
18
19
20
21
0.004
0.11
0.79
1.6
0.079
ND
1.1
>10
>10
>10
ND
2.4
1.8
2.4
1.8
1.6
5.7
1.0
1.3
0.5
4.8
H3C
H3C
H3C
N
N
N
N
O
CH3
CH3
ND
N
ND
N
H3C
H3C
H3C
N
N
CH3
CH3
3.8
ND
N
N
N
22
4.0
ND
ND
2.6
25
CH3
pocket.
In addition, the imidazopyridine and
aminopyridine rings need to be almost coplanar for a
favorable binding conformation and a 4’-substituent
causes a significant deviation from planarity.
Table 3. Scaffold hopping around the benzothiazole core. IC50, EC50
and solubility (PBS) in M (pH 7.4). Cell line: A2780 ovarian
carcinoma.
It is worth noting that compared to 6 and 9, compound 17
shows improved LLE retaining LE (6.0 and 0.49,
respectively). This suggests that while the potency
improvement in 9 may be solely driven by increased
LogP, compound 17 can achieve a similar potency in a
more polar property space, likely through a better
interaction with the hinge domain, hence the improved
LLE.
Most of the core variations led to significant potency
decrease, with the exception of imidazopyridazine 16,
demonstrating a 4-fold potency increase compared to 9,
and imidazopyridine 17, which maintained potency.
Compound 17 offered the best potency/solubility
balance, and was investigated further. Compound 17 was
potent against all PI3K isoforms, including the most
common p110 mutations, and showed mechanism
modulation and inhibition of cell proliferation in a series
of cell lines with PI3K pathway deregulation (Table 4).
It was stable in rat and human microsomes had good
permeability with low efflux potential,24 and addressed
the CYP liabilities of the benzothiazole scaffold (IC50
Compound 17 showed attractive rat PK properties with
low clearance and Vss, and oral AUC approximately 10-
fold higher than its benzothiazole analog 9 (Table 5).

IV
PO
VSS
(L/Kg)
CL
AUC
(M*h)
CMAX
(M)
#
t1/2 (h)
%F
(mL/min/Kg)
6
9
17
3.6
ND
0.68
19
ND
2
2.5
ND
3
57
ND
95
16
18
198
6
2.5
2.9
15.7
Table 5. Rat PK properties for benzothiazoles
and 9 and
imidazopyridine 17 (doses: 5 mg/kg IV and 10 mg/kg PO).
Scheme 2. Synthesis of compound 17. Reagents and conditions: (a) TsCl, Pyridine, 90 ºC, 16 h; (b) Hunig’s base, DMF, r.t., 24 h; (c) i: TFAA, DCM,
reflux, 3 h; ii: K2CO3, MeOH, 90 ºC, 16 h; iii: Acetic anhydride, pyridine, r.t.; (d) Pd(dppf)Cl2.CH2Cl2, DME, 2M Na2CO3, 120 ºC, microwave, 10 min.
various 5,6- and 6,6-fused core heterocyclic systems
led to the identification of imidazopyridine 17. This
compound had improved potency, solubility and no
CYP450 issues compared to the benzothiazoles.
Attractive rat pharmacokinetic properties warranted
further evaluation. Progress in this class of PI3K
inhibitors will be reported in due course.
Acknowledgements
The authors wish to acknowledge Frederic Stauffer
and Giorgio Caravatti for help with the in vitro
profiling of compound 17, George Thomas for
discussing in vivo pharmacokinetics and Yongjin Xu
for LE and LLE calculations.
Figure 3. Co-crystal structure of compound 17 with PI3K. Key
interactions are indicated by dotted lines.
Supplementary Data
Supplementary information associated with this article
can be found in the on line version at
www.sciencedirect.com
In conclusion, structural information on the
benzothiazole fragment hit 2 and hybridization with a
known chemotype allowed rapid biochemical and cell
potency optimization. Subsequently, a survey of
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(b) Maira, S.-M.; Pecchi, S.; Huang, A.; Burger, M.; Knapp,
M.; Sterker, D.; Schnell, C.; Guthy1, D.; Nagel, T.;
Wiesmann, M.; Brachmann, S.; Fritsch, C.; Dorsch, M.;
Chene, P.; Shoemaker, K.; De Pover, A.; Menezes, D.;
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21 PI3K IC50 = 23 M (8), PI3K IC50 = 4.2 M (1), PI3K
IC50 = >25 M (2), PI4K IC50 = 10 M (4), VPS34 IC50
=
>25 M (5). Number in parenthesis indicates number of
replicates.
22
Structure of NVP-BKM120 (1) in PI3K submitted under
PDB accession code 3SD5. Structure of compound 2 in
PI3K submitted under PDB accession code 4KZ0.
23
Ni, Z.-J.; Pecchi, S.; Burger, M.; Han, W.; Smith, A;
Atallah, G.; Bartulis, S.; Frazier, K.; Verhagen, J.; Zhang,
Y.; Iwanowicz, E.; Hendrickson, T., Knapp, M.; Merritt, H.;
Voliva, C.; Wiesmann, M.; Legrand, D.; Bruce, I. WO
2007095588.
24
For compound 6, rat MX: CL 4 g/min/mg, t1/2 187 min;
Caco-2: PappA-B (cm/sec x10-6) 46, PappB-A (cm/sec x10-6) 42.
For compound 9, rat MX: CL 8 g/min/mg, t1/2 778 min;

*Graphical Abstract (for review)