Fragment-based drug design of novel pyranopyridones as cell active and orally bioavailable tankyrase inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.5b00251

Tankyrase activity has been linked to the regulation of intracellular axin levels, which have been shown to be crucial for the Wnt pathway. Deregulated Wnt signaling is important for the genesis of many diseases including cancer. We describe herein the discovery and development of a new series of tankyrase inhibitors. These pyranopyridones are highly active in various cell-based assays. A fragment/structure based optimization strategy led to a compound with good pharmacokinetic properties that is suitable for in vivo studies and further development.

Full text of DOI:10.1021/acsmedchemlett.5b00251

Letter
pubs.acs.org/acsmedchemlett
Fragment-Based Drug Design of Novel Pyranopyridones as Cell
Active and Orally Bioavailable Tankyrase Inhibitors
Javier de Vicente,*,† Parcharee Tivitmahaisoon,† Pamela Berry,‡ David R. Bolin,† Daisy Carvajal,§
Wei He,∥ Kuo-Sen Huang,§ Cheryl Janson,§ Lena Liang,§ Christine Lukacs,§ Ann Petersen,† Hong Qian,§
Lin Yi,† Yong Zhuang,∥ and Johannes C. Hermann†
‡
∥
†Discovery Chemistry, Non-clinical Safety,§Discovery Technologies, and Discovery Oncology, Small Molecule Research, Pharma
Research & Early Development, Hoffmann-La Roche Inc., pRED, 340 Kingsland Street, Nutley, New Jersey 07110, United States
S
* Supporting Information
ABSTRACT: Tankyrase activity has been linked to the
regulation of intracellular axin levels, which have been shown
to be crucial for the Wnt pathway. Deregulated Wnt signaling
is important for the genesis of many diseases including cancer.
We describe herein the discovery and development of a new
series of tankyrase inhibitors. These pyranopyridones are
highly active in various cell-based assays. A fragment/structure
based optimization strategy led to a compound with good
pharmacokinetic properties that is suitable for in vivo studies
and further development.
KEYWORDS: Tankyrase inhibitor, fragment based drug design, structure based drug design, oncology, Wnt, axin
he Wnt signaling pathway is a major cellular pathway
also efficacious in cancer cell lines and various animal
models.14−16 While reported studies on tankyrase inhibitors
are limited to preclinical studies,16−23 we set out to discover
new drug-like TNKS inhibitors suitable for in vivo studies with
the potential for further development into clinical compounds.
We began by a biochemical screen of our in house fragment
library against TNKS1 and TNKS2. Among the many validated
hits, two sparked our interest; particularly, a pyranopyridone 1
and a benzopyrimidone 2 that share some similarity with
XAV939, one of the first published TNKS inhibitors (Table
1).14
Both compounds showed favorable ligand efficiencies of
about 0.5 with the all aromatic benzopyrimidone 2 being 10-
fold more potent. We obtained a cocrystal structure of 1
complexed with TNKS2 and were able to confidently model
the binding mode of 2 based on the publicly available crystal
structure of XAV939 bound to TNKS2 (PDB code 3KR824).25
Inspection of the overlaid structures of 1 and 2 bound to
TNKS2 (Figure 1) revealed commonalities and significant
differences. The main recognition elements of the pyridone (1)
or the pyrimidone (2) portions of the fragments to TNKS
appeared almost identical, forming hydrogen bond interactions
with Ser-1068, Tyr-1071, and Gly-1032. We hypothesized that
the cyano group in the 3-position of the pyranopyridone ring of
1 was pointing into a hydrophobic spot of the pocket where it
T
controlling multiple biological processes.1 The final step
in Wnt signaling is characterized by either proteolysis of the
transcription factor β-catenin (Wnt signaling “on”) or the
prevention of its proteolysis resulting in β-catenin dependent
gene transcription (Wnt signaling “off”). The Wnt dependent
β-catenin destruction complex is assembled by adenomatous
polyposis coli (APC), axin, and glycogen synthase kinase 3α/β
(GSK3α/β). The formation of the destruction complex relies
on the availability of all its constituents with axin as the rate
limiting component.2 Overexpression of axin has been shown
to counteract effects of nonfunctional APC and to cause
degradation of β-catenin.3 Many cancers have artificially high
Wnt signaling.4−6 This is often caused by mutations; for
example, colorectal cancers are characterized by mutations in
the APC protein that prevent it from forming the β-catenin
destruction complex.7−9 Targeting Wnt is therefore of interest
for the potential treatment of various diseases including
cancer.10−12
Regulation of axin levels is important for any cell as it has
direct consequences on Wnt signaling. Axin2 is directly
regulated through Wnt signaling itself, as its transcription is
dependent on β-catenin.13 Tankyrase enzymes 1 and 2
(TNKS1 and TNKS2), also called Poly ADP Ribose Polymer-
ase (PARP) 5a and 5b, respectively, are important regulators of
intracellular axin levels as they catalyze poly-ADP-ribosylation
of axin, which subsequently leads to ubiquitination and
degradation.14 Recently discovered small molecule inhibitors
of TNKS not only showed the ability to protect axin from
degradation and to raise intracellular axin levels, but they were
Received: June 23, 2015
Accepted: August 4, 2015
© XXXX American Chemical Society
A
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prepared (Scheme 1), which not only showed improved
potency (Table 2), but remarkably also increased the already
Table 1. Structures and Biochemical Activity of Initial
Fragment Hits
a
Scheme 1. Synthetic Route to Pyranopyridones
a
Throughout our optimization efforts we determined activities for
TNKS1 and TNKS2. Since the activity of compounds against either
enzyme changed similarly upon structural modifications, we will refer
from here on only to the slightly less active TNKS2 activities. Full
activity profiles for each compound are given in Table S1.
a
Reagents, conditions, and yields (a) (i) TFA, CH2Cl2, rt; (ii) K2CO3,
MeOH, rt, 63−94%; (b) PCC, SiO2, CH2Cl2, rt, 73−83%; (c) (i)
Pd2dba3, Xantphos, Cs2CO3, MW 90 °C; (ii) 7N NH3 in MeOH, MW
140 °C 4−40%; (d) TFA, 140 °C, 77%; (e) EDCI, oxetane-3-
carboxylic acid, DIPEA, DMF, rt, 46%; (f) acetyl chloride, MeOH, 0
°C to rt, 99% (g) methansulfonyl chloride, NMP, rt, 43%; (h)
Pd(OH)2 20 wt %, HCl (cat), 1:1 dioxane/EtOH, 24%; (i) Pd(OH)2
20 wt %, HCl (cat), dioxane, 92%.
very desirable ligand efficiency of 2 to at least 0.56. Compound
3 was also reasonably potent in a functional luciferase cell based
assay with an EC50 of 320 nM, suggesting favorable membrane
permeability. However, the in vivo pharmacokinetic study
(Table 2) in rats for this compound showed moderate to high
clearance of 37 mL/min/kg consistent with the high intrinsic
clearance predicted by rat liver microsomes.
The novel pyranopyridones were rapidly assembled in three
steps (a−c, Scheme 1). A standard Prins cyclization of 3-buten-
1-ol with commercially available aldehydes effectively yielded
the 2-substituted pyrane building blocks. The alcohol at the 4-
position was oxidized to a ketone with PCC. The final
pyranopyridone scaffold was constructed by a palladium
mediated regioselective ketone C-arylation to yield a tricyclic
coumarine, which upon treatment with ammonia afforded the
desired pyranopyridones.
Having established a concise synthesis of pyranopyridones,
we set out to improve clearance, solubility, and cell potency
with a focus on metabolic stability (Table 2). Aided by crystal
structures, we aimed to increase solubility and possibly reduce
clogP by introducing side chains and modifications consistent
with our understanding of the binding site properties. In
general, two areas seemed attractive for modifications of the
initial pyranopyridone 3; the fused phenyl ring and the
isopropyl side chain on the other end of the molecule.
Although the fused phenyl ring portion is located in a narrow
subpocket pointing toward a small exit channel of the binding
Figure 1. Crystal structure of 1 (carbon atoms in orange) bound to
TNKS2 with 2 (carbon atoms in yellow) modeled in the active site
and overlaid.26 Oxygen atoms are in red (cyan for water molecules),
nitrogen atoms in blue, and chlorine in green.
was not contributing to the binding affinity of the ligand. In
contrast, the fused phenyl ring of the benzopyrimidone 2
maintains hydrophobic interactions. The aromatic ring is well
packed with Tyr-1071 on one side in a skewed type face-to-face
π-interaction and the Cβ-methylene group of Tyr-1060 on the
opposite side. We were excited to see that the oxygen of the
pyrane ring of 1 was accepting a hydrogen bond from a
conserved water molecule that is tightly bound to Tyr-1060 and
His-1048 (distance 3 Å). We decided to keep the pyrane ring in
molecule 1 thereby maintaining the aliphatic sp3 atoms in the
scaffold and then replace the cyano group. The overlay
suggested that merging the two fragments by incorporating
the phenyl portion of the ∼10× more potent benzopyrimidone
core scaffold into the pyranopyridone in place of the nitrile
group would be favorable. Subsequently compound 3 was
B
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Table 2. Activity, Physicochemical, and DMPK Properties of Pyranopyrimidones
a
b
c
Compounds 3−10 are racemic, and all the reported in vitro and in vivo data is with the racemic form. LYSA kinetic solubility.27 Category of
predicted clearance: low < 14 μL/min/mg; medium = 14−80 μL/min/mg; high > 80 μL/min/mg.
site, this subpocket displays minor patches where hydrophilic
interactions seem possible, e.g., Glu-1138, Ser-1068, and Asn-
1064 (with bound water molecule). Modifications of the phenyl
ring led to many compounds with improved properties;
C
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however all of them showed loss of activity. One of the more
promising compounds was the pyridine replacement 4, which
displayed slightly improved solubility (13 μg/mL), much better
in vivo rat clearance (10 mL/min/kg), and only a 3-fold loss in
cell potency.
group moiety and remains empty or is filled by a water
molecule that is offered only hydrophobic atoms for interaction.
Filling this space with a small hydrophobic group like the
methyl was thought to occupy this space perfectly, thereby
potentially releasing an unfavorably bound water molecule. The
improved potency of compounds bearing a methyl in that
position may support this design hypothesis.
The other area of modification, the isopropyl group, projects
into an area where the binding site widens and allows larger
side chains to fit. Many more interesting compounds were
discovered by redesigning and replacing the isopropyl side
chain, as exemplified by compounds 5, 6, and 7. These types of
compounds had similar or up to 10-fold higher cell potency,
improved solubility, and often lower in vitro and in vivo
clearance. The t-butyl compound 8 was discovered when trying
to maximize the immediate hydrophobic contact next to the
scaffold. Compound 8 was as predicted very potent but also
surprisingly stable with a clearance of about 2 mL/min/kg. The
low solubility of 8 led us to introduce hydrophilic solubilizing
groups into the t-butyl. This area of the binding site seemed like
it would tolerate hydrophilic groups of different sizes since it
contains not only hydrophilic interaction surfaces but also
many bulk and crystal water molecules to interact with. The
most intriguing compound from this exercise was compound 7.
Compound 7 retained all of the positive properties from
compound 8 and had improved solubility of 66 μg/mL. The
compound lacked high cell potency (341 nM), but that could
have been potentially overcome by higher dosing and/or
alternative routes of administration (e.g., i.p.). However, during
the exploration of the fused phenyl ring of the scaffold we
discovered a “magic methyl” (compound 9), which did not
improve properties, but boosted the potency by about 100-fold
each time we introduced this motif into any of our more
evolved compounds. Introduction of the methyl group into
compound 7 led to compound 10, which also showed vastly
increased potency to 7 nM in cells (Figure 2).
The methyl group in compound 10 provided the expected
potency boost but caused a significant drop in solubility as
compared to compound 7. Hence the compound was further
profiled in biorelevant FASSIF and FESSIF media solubility
studies that revealed reasonable solubility at 50 and 143 μg/mL,
respectively. The CACO2 permeability assay data for 10 (26 ×
10−6/sec) indicated that the compound was highly permeable.
Given the promising results thus far for compound 10, it was
decided to advance it into more in depth activity studies. We
tested its ability to prevent axin degradation in an APC mutant
cell line (DLD1). This study revealed that compound 10 was
able to prevent the enhanced axin degradation in that cell line
in a dose-dependent manner (graphical representation, Figure
3a). We then investigated whether or not compound 10 was
able to inhibit mRNA production of β-catenin-dependent target
genes such as Axin2 and TNFRSF19. Dose-dependent
inhibition of expression was observed for both genes with
compound 10 (Figure 3b).
Since these results showed that compound 10 was acting on
target in a dose-dependent manner in cell based assays, we fully
The magic methyl fits nicely in a very small pocket, which is
space limited on three sides by tyrosine residues Tyr-1050, Tyr-
1060, and Tyr-1071 (Figure 2). In compounds lacking the
methyl, this space is also bordered by the compound’s phenyl
Figure 3. Axin protective effect of compound 10 in the APC mutant
cell line DLD1. (A) Graphical gel representation of lack of axin1 and
axin2 degradation. Controls are DMSO and tankyrase independent β-
actin. (B) Dose-dependent inhibition of β-catenin target genes by
compound 10. Axin2 and TNFRSF19 expression is measured through
qRT-PCR.
Figure 2. Overlapping X-ray crystal structures of compounds 9 and 7
bound to TNKS2 showing the potency boosting methyl group.
Compound 7 has carbon atoms colored in gold, 9 in green; oxygen
atoms are in red (cyan for water molecules), and nitrogen atoms are
colored blue.26
D
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profiled 10 for its pharmacokinetic properties (Table 3) in
order to assess its promise as an in vivo tool compound.
ACKNOWLEDGMENTS
■
We gratefully thank Santina Russo and Joachim Diez of Expose
GmbH for synchrotron data collection. This work was
supported exclusively by Hoffmann-La Roche.
Table 3. Single Dose Pharmacokinetic Parameters of
Compound 10 in Male C57BL/6J Mice
ABBREVIATIONS
parameter
Tmax (h)
1 mg/kg iv
5 mg/kg po
50 mg/kg po
■
TNKS1, Tankyrase 1; TNKS2, Tankyrase 2; LYSA, lyophiliza-
tion solubility assay; FASSIF, fasted-state simulated intestinal
fluid; FESSIF, fed-state simulated intestinal fluid; APC,
adenomatous polyposis coli; TCF, T-cell factor
0.25
1.6
1.4
49
0.25
14
Cmax (μg/mL)
AUC0‑last (μg·h/mL)
F (%)
0.6
27
92
Cl ((mL/min)/kg)
Vdss (L/kg)
28
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsmedchem-
lett.5b00251.
■
S
Full synthetic details and characterization of synthetic
intermediates and final products for all compounds
described, enzymatic assay data for compounds 1−10,
crystallographic data details, and full description of
pharmacokinetic studies and physicochemical assays
(PDF)
Accession Codes
Structures are deposited in the RCSB Protein Data Bank under
5C5R, 5C5P, and 5C5Q (compounds 1, 7, and 9, respectively).
AUTHOR INFORMATION
Corresponding Author
*Phone: 510-879-9321. E-mail: vicente_javier@hotmail.com.
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Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
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