Design and discovery of 2-arylquinazolin-4-ones as potent and selective inhibitors of tankyrases

Article abstract of DOI:10.1021/ml400260b

Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC₅₀ = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4′-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

Full text of DOI:10.1021/ml400260b

Letter
pubs.acs.org/acsmedchemlett
Design and Discovery of 2‑Arylquinazolin-4-ones as Potent and
Selective Inhibitors of Tankyrases
Amit Nathubhai, Pauline J. Wood, Matthew D. Lloyd, Andrew S. Thompson, and Michael D. Threadgill*
Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom
S
* Supporting Information
ABSTRACT: Tankyrases (TNKSs) are poly(ADP-ribose)polymerases
(PARPs) that are overexpressed in several clinical cancers. They regulate
elongation of telomeres, regulate the Wnt system, and are essential for the
function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been
designed and identified as potent and selective TNKS inhibitors, some being
more potent and selective than the lead inhibitor XAV939, with IC50 = 3 nM
vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the
4-position of the 2-phenyl group; electronic effects and H-bonding were
irrelevant, but charge in the 4′-substituent must be avoided. Molecular
modeling facilitated initial design of the compounds and rationalization of
the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further
development into anticancer drugs.
KEYWORDS: Tankyrase, quinazolin-4-one, PARP, selectivity, hydrophobic pocket
ankyrase-1 (PARP-5a, TNKS-1, ARTD5) and tankyrase-2
contains homopolymeric tracts of His, Pro, and Ser; this is
T(PARP-5b, TNKS-2, ARTD6) are members of the absent from TNKS-2.2,16 Some of their functions are specific to
one or other isoform, but the two tankyrases can act
redundantly for many. Thus, in designing a therapeutic
inhibitor, selectivity with respect to other NAD+-binding
enzymes (e.g., other PARPs and oxidoreductases) is desirable
but selectivity between the tankyrases is not.
poly(ADP-ribose)polymerase (PARP) superfamily of enzymes.
PARPs transfer ADP-ribose units from substrate NAD+ to
acceptor proteins, building poly(ADP-ribose) polymers.1
TNKS-1 was first reported in 1998;2 it is responsible for
regulating the (re)elongation of telomeres through poly(ADP-
ribosyl)ation of telomere repeating binding factor-1 (TRF-1)
and autopoly(ADP-ribosyl)ation.3,4 Tankyrases have been
proposed to be therapeutic targets in cancer on the basis of
this role at telomeres, leading the cells into telomere-shortening
crisis, much in the manner of telomerase inhibitors.5 Tankyrase-
1 is also required for correct structure and function of the
mitotic spindle and centrosome, where the main protein
substrate is NuMA.6 Aberrant Wnt signaling is involved in
many human cancers, and inhibitors of this system show
antitumor activity in vivo.7,8 The specific protein target for
poly(ADP-ribosyl)ation by tankyrases in the Wnt system is
axin, stimulating its degradation through the ubiquitin-
proteasome pathway. Thus, inhibition of tankyrases results in
prolonged life of axin and increases the amount of the
destruction complex of β-catenin. This leads to decreased levels
of β-catenin and increased levels of phosphorylated β-catenin
causing inhibition of the Wnt/β-catenin-driven proliferation of
cancer cells.9
A few tankyrase inhibitors have been reported to date.
XAV939 1 (Figure 1) was identified by high-throughput
screening as an inhibitor of Wnt signaling; it was subsequently
confirmed that this effect was due to potent and selective
inhibition of the tankyrases.9 This compound is reported to
show IC50 vs TNKS-1 = 11 nM and IC50 vs TNKS-2 = 4 nM, in
contrast to IC50 = 2.3 μM for inhibition of PARP-1. This
compound has since been used as a molecular tool to study the
Wnt pathway and its role in cancer and other cellular
functions.17−20 Inhibitors of varying potency have also been
identified, which bind at the adenosine-binding and other
sites.21−23 Very recently, some quinazolin-4-ones carrying
(CH2)2CONHAr at position-2 have been reported as binding
both to the nicotinamide-binding site and at an induced
pocket.24
A crystal structure of 1 bound into the nicotinamide-binding
region of the catalytic domain of TNKS-2 was published in
2010,25 revealing the classical PARP motif of H-bonding of the
lactam carbonyl O with OH of Ser1068 and with NH of Gly1032
and of the lactam NH with CO of Gly1032. Further π-stacking
interactions are made from the lactam to Tyr1071, and the side-
Tankyrases are overexpressed in several human cancers,
including breast cancer,10 colon cancer,11 chronic myeloid
leukemia,12 brain tumors,13 and gastric14 and bladder cancers.15
There is 85% sequence homology between TNKS-1 and
TNKS-2 within the ankyrin repeat, sterile alpha motif, and the
NAD+-binding catalytic domains; the catalytic domains are 86%
identical. TNKS-1 contains an N-terminal HPS domain, which
Received: July 9, 2013
Accepted: October 15, 2013
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
Letter
Using 1 as a structural lead and the above crystal structure25
as a basis for structure-based design, we designed a series of 2-
arylquinazolin-4-ones as potential inhibitors of the tankyrases.
In our target quinazolinones, the 2-aryl group is variously
substituted at the 4-position, as the modeling guided us that the
benzene ring would fit well into a hydrophobic pocket lined
with Tyr1050, Tyr1060, and Pro1034. In this pose, the 4-
substitutent on the benzene ring projects into a smaller
hydrophobic tunnel, flanked by Phe1035 and Ile1075. The model
showed that substitution would not be tolerated at the 5-, 6-,
and 7-positions of the quinazolin-4-one but that small groups at
the 8-position may be acceptable. Clearly, the lactam is
designed for H-bonding to Gly1032 and Ser1068
.
The quinazolin-4-ones were prepared by classical methods
(Scheme 1). 2-(4-Chlorophenyl)quinazolin-4-one 3 was
synthesized in moderate yield in one pot by condensation of
anthranilamide 2 with 4-chlorobenzaldehyde in the presence of
hydrogensulfite ion, with air oxidation of the intermediate
aminal occurring in situ. The corresponding 3-methyl- and 3-
methoxyanthranilamides 5a,b were prepared by reaction of the
acids 4a,b with carbonyldiimidazole, followed by aqueous
ammonia.26 Acylation of 5a,b with a range of 4-substituted
benzoyl chlorides furnished the 3-methyl-2-aroylaminobenza-
mide derivatives 6a,b in excellent yields. Finally, cyclization of
6a,b under basic conditions provided 7a−i in good to excellent
yields. The para-substituents on the 2-phenyl ring of
quinazolin-4-ones 7a−i range from electron-donating to
electron-withdrawing but lack potential for H-bond donation.
Transfer hydrogenation of the nitro group of 7d gave the
primary aniline of 7j. Demethylation of the methoxyphenyl
group of 7e provided the corresponding phenol in 7k. To test
Figure 1. Structure of XAV939 1 and representation of the X-ray
crystal structure of 1 bound into the NAD+-binding catalytic domain
of human tankyrase-2.25 Key protein residues are in gray, and key H-
bond interactions are shown as green dashed lines.
chain trifluoromethylphenyl projects into a hydrophobic
pocket, π-stacking with Tyr1050 and making hydrophobic
interactions with Pro1034, Phe1035, and Ile1075. Our interpretation
of the binding of 1 in the crystal of tankyrase-2 is shown in
Figure 1.
a
Scheme 1. Syntheses of Target 2-Arylquinazolin-4-ones 3, 7, and 11 and Locant Numbers
a
Reagents and conditions: i, PhCHO, NaHSO3, AcNMe2, 150 °C, open flask; ii, CDI; iii, aq. NH3; iv, ArCOCl, pyridine; v, aq. NaOH (0.5 M),
+
−
60°C; vi, NH4HCO2 , Pd/C, MeOH, DMF; vii, BBr3, CH2Cl2 reflux; viii, CbzCl, aq. K2CO3; ix, SOCl2; x, 5a, pyridine; xi, aq. K2CO3 (1.0 M),
100°C; xii, HBr, AcOH.
B
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the acceptability of a H-bond donor at the 8-position, 7i was
similarly demethylated to afford the 8-hydroxyquinazolin-4-one
7l. To challenge the dimensions of the hydrophobic pocket, the
4-substituent of the phenyl ring was extended in 10. 4-
Aminomethylbenzoic acid 8 was acylated at N with benzyl
chloroformate under Schotten−Baumann conditions, before
formation of the acyl chloride. This was used to acylate the
anthranilamide 5a, providing the intermediate amide 9. The
usual cyclization conditions of hot aqueous sodium hydroxide
merely hydrolyzed the carbamate, but treatment with the
weaker base potassium carbonate cyclized 9 smoothly to give
10. Removal of Cbz with HBr gave 11, which tested the
tolerance of a basic amine (i.e., cation) in the 4′-position.
Compounds 3, 7f, 7i, and 7l test the required nature of the 8-
substituent (H, Me, OMe, and OH, respectively), while keeping
the 2-aryl group constant as 4-chlorophenyl. Similarly, the
requirements for the 4-substituent are explored while keeping
the 8-substituent constant as methyl (in 7a−l, 10, and 11). The
members of this library were then evaluated for potency of
inhibition of the catalytic activities of human TNKS-1 and
TNKS-2, with counterscreening for selectivity against PARP-1
and a representative NAD+-requiring oxidoreductase, inosine
monophosphate hydrogenase-2 (IMPDH2, itself the target of
the active metabolite TAD of the experimental agent
tiazofurin27 and metabolites of therapeutic 6-thioguanine and
6-mercaptopurine28).
Table 1. IC50 Values for Inhibition of Enzyme Activity by
Test 2-Arylquinazolin-4-ones
TNKS-1 IC50
(nM)
TNKS-2 IC50
(nM)
PARP-1 IC50
(nM)
IMPDH2 IC50
compd
(μM)
1
17
42
35
48
32
37
36
32
44
35
52
73
9.6
41
1200
795
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
7a
7b
7c
7d
7e
7f
6.7
10
685
a
>5000
30
104
891
12
a
33
>5000
a
7g
7h
7j
5.5
40
>5000
a
>5000
3.3
5.5
44
504
7k
10
11
1200
a
>5000
b
b
b
ND
∼100
ND
ND
a
b
Limited by solubility. Not determined.
increasing the size of the 4′-substituent greatly, in 10, only
results in slight loss of potency against TNKS-2 (10, IC50 = 44
nM; cf., 7k, IC50 = 3 nM, and 7a, IC50 = 41 nM). However, the
primary aliphatic amine in 11, which would be protonated and
cationic at the pH of the assay, caused major loss of activity
against TNKS-2.
Compounds were evaluated for inhibition of autopoly(ADP-
ribosyl)ation activity of TNKS-2 using an assay developed in
house. Full details are given in the Supporting Information.
Compounds 3, 7f, 7i, and 7l, which differ only in the 8-
substituent on the quinazolin-4-one core, were assessed for
inhibition at one concentration, 10 nM. These data (3, 2 5%;
7f, 49 14%; 7i, 25 5%; 7l, 32 2% inhibition) showed that
methyl is the 8-substituent giving the greatest potency. Further
detailed studies were conducted keeping the 8-methyl group
constant, while varying the 4-substituent on the 2-aryl group.
IC50 values were then determined for inhibition of TNKS-2 by
the focused library of 8-methylquinazolin-4-ones 7a−h,j,k, 10,
and 11. These compounds were also examined for their ability
to inhibit the activity of the isoform TNKS-1, using a
commercial assay in which the enzyme transfers biotinylated
ADPr units to immobilized histone-1. Two counterscreens
were also used to assess the selectivity of inhibition of the
tankyrases by the test compounds: PARP-1 and IMPDH2. The
data are presented in Table 1.
The standard inhibitor 1 showed IC50 values comparable
with those reported9 using a different assay. We determined 1
to be 71-fold selective for inhibition of TNKS-1 and 133-fold
selective for TNKS-2, both vs. PARP-1. Our 2-aryl-5-
methylquinazolin-4-ones all showed potent and selective
inhibition of the tankyrases. Compounds 7a−h,j,k were
marginally less potent against TNKS-1 than was 1, with IC50
values very similar to each other at ca. 40 nM. These
compounds were generally more potent against TNKS-2,
with 7b (4′-Me), 7g (4′-Br), 7j (4′-NH2), and 7k (4′−OH)
having lower IC50 values than did 1. Some structure−activity
relationship (SAR) inferences can be drawn for the 4′-position.
Very small substituents (H in 7a, F in 7h) reduce the activity
significantly, with smaller effects of Cl in 7d and NO2 in 7f. The
most potent compounds 7b,c,e,g,j,h carry similarly sized
substituents; size appears to be much more important than
electronic or polar/H-bonding properties (the aniline in 7j and
the phenol in 7k would not be ionized). Interestingly,
The counterscreen against PARP-1 used a commercial kit
(Trevigen). All the 2-aryl-8-methylquinazolin-4-ones showed
modest inhibition of PARP-1, up to the limit of solubility
(Table 1). Some inhibitors showed equivalent or improved
selectivity for tankyrases over PARP-1, compared with 1. For
example, the 4′-CF3 analogue 7c was >100-fold and >500-fold
selective for TNKS-1 vs. PARP-1 and TNKS-2 vs PARP-1,
respectively; 7g (4′-Br) was >150-fold and >830-fold selective,
respectively; 7j (4′-NH2) was 14-fold and 170-fold selective,
respectively; 7k (4′-OH) was 23-fold and 240-fold selective,
respectively. Even 10, with the very long 4′-group, showed
good selectivity (>70-fold TNKS-1 vs. PARP-1, >110-fold
TNKS-2 vs. PARP-1). These modest activities vs. PARP-1
correlate well with data for 7a,c−e,j,k reported by Griffin et
al.29 who investigated quinazolin-4-ones as PARP-1 inhibitors.
The known inhibitor 1 and our new potent tankyrase
inhibitors were counterscreened against IMPDH2, an oxidor-
eductase that uses NAD+, to examine selectivity further. No
inhibitory activity was seen for 1 and for 7a−h,j,k and 10 up to
10 μM (Table 1), indicating extremely high selectivity for these
compounds for the tankyrases over IMPDH2. This is expected,
as tiazofurin itself is inactive but must be metabolized to TAD
for potent inhibition.27
To aid in understanding of the mode of binding and of the
SARs, the structures of selected quinazolin-4-ones were docked
into the nicotinamide-binding site of tankyrase-2 (containing
1), using the published crystal structure.25 Structures of the
quinazolin-4-ones were minimized and charged using Sybyl and
were docked onto the protein using the lactam as a fixed
feature. The ligands were subjected to molecular dynamics and
molecular mechanics optimization. The upper four panels of
Figure 2 show the structures of four 2-(4-chlorophenyl)-
quinazolin-4-ones with different 8-substituents bound into this
site. In 7f (8-Me), 7i (8-OMe), and 7l (8-OH), the small 8-
substituents project into a small pocket in the protein surface,
whereas this pocket is unoccupied when 3 (8-H) is bound. The
methoxy group in 7i is carefully angled to project the methyl
C
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ACS Medicinal Chemistry Letters
Letter
substituents, irrespective of polarity or H-bonding, but its lining
is intolerant of the highly polar cation in 11. Most interesting is
the binding of 10. The long CbzNHCH2 group threads through
the tunnel, placing the remote benzene ring in solvent where it
interacts with hydrophobic residues Ile1075, Tyr1050, and Ile1051
on the protein surface. The CbzN−H makes a partly occupied
H-bond (2.9 Å O−N) with Ala1052 carbonyl in the tunnel,
pointing to further opportunities for design of second-
generation inhibitors.
Here, we report the design and early evaluation of a series of
2-arylquinazolin-4-ones as potent and highly selective inhibitors
of the tankyrases, important new target enzymes for cancer
treatment. Methyl at the 8-position appears to be optimum for
potency, and a variety of substituents are tolerated at the para-
position of the 2-phenyl ring. These quinazolin-4-ones are
highly selective for inhibition of tankyrases-1 and -2, showing
much weaker inhibition of the most abundant PARP, PARP-1,
and no effect whatsoever on an NAD+-requiring oxidoreduc-
tase, IMPDH2. Molecular modeling revealed the structural
basis of potency and selectivity in which the 2-aryl group was
accommodated in a hydrophobic pocket from which a narrow
tunnel leads to the solvent. These compounds provide
important leads for design and development of pharmaceuti-
cally useful drugs for treatment of cancer and other diseases.
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of chemical syntheses, characterization of inhibitors,
biochemical methods and IC50 curves, etc. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*(M.D.T.) Tel: +44 1225 386840. Fax: +44 1225 386114. E-
mail: m.d.threadgill@bath.ac.uk.
■
Funding
The authors thank the Association for International Cancer
Research for generous financial support.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Lari Lehtio (University of Oulu) for helpful
̈
Figure 2. Molecular modeling of 2-arylquinazolin-4-one inhibitors into
the structure of the nicotinamide-binding site of tankyrase-2. The
upper four panels compare the binding of the 8-substituent while
keeping the 2-aryl group constant. The lower five panels show the
location of the 2-aryl group in the hydrophobic pocket, placing the 4′-
substituent in a narrower tunnel through to solvent water.
discussions.
ABBREVIATIONS
■
ADP, adenosine-diphosphate-ribose; Cbz, benzyloxycarbonyl;
IMPDH, inosine monophosphate dehydrogenase; NAD+,
nicotinamide adenine dinucleotide; PARP, poly(ADP-ribose)-
polymerase; TAD, tiazofurin adenine dinucleotide; TNKS,
tankyrase; TRF-1, telomere repeating binding factor-1
further into this pocket. These observations explain the weaker
activity of 3 at 10 nM, compared with 7f,i,l.
The lower five panels of Figure 2 show the binding of five
quinazolin-4-ones with the same 8-substitutent (Me) but with
five different 4′-substituents on the 2-phenyl group. The 2-aryl
groups project into the center of a large hydrophobic pocket,
lined with aromatic residues. On the opposite face of the
pocket, there is a narrower hydrophobic tunnel leading through
to solvent water; the lower five panels of Figure 2 show the
views from the exterior through the tunnel into the
hydrophobic pocket. The 2-phenyl fits the large pocket snugly;
the small 4′-substituents are then located in the inner end of
the tunnel. This local environment tolerates moderately narrow
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