GDC-0449-A potent inhibitor of the hedgehog pathway

Article abstract of DOI:10.1016/j.bmcl.2009.08.049

SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of functionalized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were optimized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as 12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh pathway for growth and is currently in human clinical trials, where it is initially being evaluated for the treatment of BCC.

Full text of DOI:10.1016/j.bmcl.2009.08.049

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5576–5581
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
GDC-0449—A potent inhibitor of the hedgehog pathway
b
a
a
a
Kirk D. Robarge a, , Shirley A. Brunton , Georgette M. Castanedo , Yong Cui , Michael S. Dina ,
Richard Goldsmith a, Stephen E. Gould c, Oivin Guichert c, Janet L. Gunzner a, Jason Halladay a, Wei Jia a,
Cyrus Khojasteh a, Michael F. T. Koehler a, Karen Kotkow c, Hank La a, Rebecca L. LaLonde a, Kevin Lau a,
Leslie Lee a, Derek Marshall a, James C. Marsters Jr. a, Lesley J. Murray a, Changgeng Qian c, Lee L. Rubin c,
Laurent Salphati a, Mark S. Stanley a, John H. A. Stibbard b, Daniel P. Sutherlin a, Savita Ubhayaker a,
Shumei Wang a, Susan Wong a, Minli Xie a
*
a Genentech, Small Molecule Drug Discovery 1 DNA Way, South San Francisco, CA 94080, United States
b Evotec, 114 Milton Park, Abingdon, Oxfordshire OX14 4RX, United Kingdom
c Curis Inc., 45 Moulton Street, Cambridge, MA 02138-1118, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
SAR for a wide variety of heterocyclic replacements for a benzimidazole led to the discovery of function-
alized 2-pyridyl amides as novel inhibitors of the hedgehog pathway. The 2-pyridyl amides were opti-
mized for potency, PK, and drug-like properties by modifications to the amide portion of the molecule
resulting in 31 (GDC-0449). Amide 31 produced complete tumor regression at doses as low as
12.5 mg/kg BID in a medulloblastoma allograft mouse model that is wholly dependent on the Hh path-
way for growth and is currently in human clinical trials, where it is initially being evaluated for the treat-
ment of BCC.
Received 10 July 2009
Revised 9 August 2009
Accepted 11 August 2009
Available online 15 August 2009
Keywords:
GDC-0449
Hedgehog pathway
Small molecule inhibitor
Ó 2009 Elsevier Ltd. All rights reserved.
The focus of cancer research has shifted in recent years from
agents that act on rapidly dividing cells to molecules that target
specific proteins and pathways that are misregulated in tumors.
Molecules acting with such specificity are potentially less toxic
to normal cells that do not rely on these pathways to survive, while
maintaining or improving efficacy. One subset of these oncology
targets involves genes ordinarily active during embryonic develop-
ment which are abnormally reactivated in adults through sporadic
mutation. This reactivation can lead to tumor growth.
In the case of the Hedgehog (Hh) pathway, the 12 transmem-
brane receptor patched (PTCH) is a negative regulator of the seven
transmembrane receptor smoothened (SMO). PTCH is the receptor
for the Hh ligand and inhibits SMO until the Hh ligand binds,
allowing SMO to signal. Through an intracellular pathway that is
still incompletely understood, this signaling event results in the
nuclear translocation of the Hh transcription factors Gli1 and
Gli2, which initiate transcription of Hh responsive genes
(Fig. 1).1,2 During development, this pathway is responsible for
embryonic patterning in a variety of tissues. In patients afflicted
with Gorlin Syndrome, a mutation of the negative regulator, PTCH,
causes uncontrolled SMO signaling producing multiple basal cell
carcinomas (BCC)3,4 along with much higher growth rates of other
cancers. There is also strong evidence linking alterations in the Hh
pathway to sporadic BCC,5,6 medulloblastoma,7,8 small cell lung,9
and gastro-intestinal tract cancers,10 among others.
The Hh pathway has been studied extensively using the natural
product cyclopamine, a steroidal alkaloid that blocks Hh signaling
with an EC50 of approximately 300 nM and has been shown to bind
SMO,11 to modify Hh pathway activation in cell cultures,12 and to in-
hibit the proliferation of human medulloblastoma8 and basal cell
* Corresponding author. Tel.: +1 650 225 2320.
E-mail address: kir@gene.com (K.D. Robarge).
Figure 1. Diagram of Hedgehog signaling.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.049

K. D. Robarge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5576–5581
5577
carcinoma13 skin explants. However, cyclopamine has limitations as
a viable therapeutic agent. Its structural complexity, scarcity, poor
aqueous solubility, and poor chemical stability in acid led us to iden-
tify small molecule Hh antagonists of a different chemical class.
A high-throughput screen was performed based on murine
10T1/2 (S12) embryonic fibroblast cells containing a plasmid with
a luciferase reporter gene downstream of Gli binding sites. When
these cells are stimulated with Sonic Hh (Shh), the luciferase activ-
ity can be measured optically. Hh pathway antagonists reduce the
magnitude of this signal.13–15 Hit-to-lead optimization of the
screening hits produced benzimidazole 1 (Table 1), which had
attractive potency in a Hh pathway assay. Others have reported
that a structurally similar benzimidazole antagonist of the Hh
pathway displaces fluorescently labeled cyclopamine from
SMO,16 leading us to believe that 1 might act in a similar fashion.
Compound 1 had several important weaknesses as a drug can-
didate. A primary concern was its poor metabolic stability in dogs
that tracked with the high predicted clearance (22 mL/min/kg)
from incubation with dog liver microsomes (Table 3) coupled with
a high predicted clearance in human (9.4 mL/min/kg) from incuba-
tion with human microsomes. Additionally, the aqueous solubility
was low at 0.3 lg/ml at pH 6.5. We began our investigation by tar-
geting a wide variety of replacements for the benzimidazole, rea-
soning that we could rapidly modify the amide portion of any
promising cores.
Two key intermediates enabled the synthesis of the majority of
our heterocyclic replacements. 2-Chloro-5-nitro-acetophenone
was obtained from the nitration of 2-chloroacetophenone and then
Table 1
SAR exploring heterocycle replacements
converted to the
a-bromo ketone to produce imidazothiazole 9,
Cl
O
Me
R
N
N
Table 1 (continued)
H
CF3
Entry
R
Gli LUC S12 IC50
0.256
(lM)
Entry
R
Gli LUC S12 IC50
0.012
(lM)
N
11
12
13
14
15
16
17
18
19
20
N
N
H
Me
1
N
H
N
0.450
9.000
0.550
0.042
10.00
2.400
8.000
1.700
0.052
N
2
3
4
5
6
0.500
0.009
0.150
0.070
0.170
N
H
N
N
HN
Me
N
Me
N
N
N
N
N
Me
N
S
N
N
N
N
N
7
8
9
0.080
4.200
0.200
N
N
N
N
N
N
S
N
N
NH
O
N
10
0.140
N
(continued on next page)

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K. D. Robarge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5576–5581
pyrazine 19, and quinoxaline 20 (Scheme 1). Formation of indoli-
zine 8 required initial reduction of the nitro and coupling of the
2-methyl-6-trifluoromethyl nicotinic acid portion before the het-
erocycle could be formed.
that of 1 was 4.16.18 The requirement for a basic nitrogen adjacent
to the ring fusion is also observed in the single ring replacements
for the benzimidazole. The only single ring replacement for the
benzimidazole with an IC50 less than 50 nM is the 2-pyridyl com-
pound 15. As would be predicted from the bicyclic analogs, the reg-
ioisomeric 3-and 4-pyridines 16 and 17 were significantly less
potent. Pyrazole 12 showed only moderate potency, which was
greatly reduced in the regioisomeric 13, presumably because one
of its tautomeric forms cannot serve as a hydrogen bond acceptor.
When the pyrazole is methylated, as in 14, preventing the tauto-
merization, the potency is restored.
The second trend in the SAR was a preference for an aromatic
ring fused to the nitrogen containing heterocycle. Imidazole 11,
for example, is greater than 20-fold less potent than the corre-
sponding benzimidazole 1. Similarly, the saturated tetrahydro-
benzimidazole 4 was found to be almost 17-fold less potent than
3 and pyrazine 19 is 32-fold less potent than quinoxaline 20.
Having developed a group of possible replacements for the
benzimidazole portion of the molecule, we sought to optimize
the amide portion of our biaryls. Compound 3 was the most potent
but was not further considered due to moderate CYP inhibition
A second group of benzimidazole replacements were synthe-
sized from 2-chloro-5-nitroaniline, which was converted to the
isomeric pyridines 15, 16, and 17 as well as the pyrimidine 18
(Scheme 2) through conversion of the aniline to a halogen and sub-
sequent coupling to the desired heterocycle. Alternatively, diazoti-
zation and reduction to the corresponding hydrazine gave rise to
the pyrazole in 12. The indazole in 7 was obtained by forming an
imine with 2-nitrobenzaldehyde and subsequent reduction of the
adjacent nitro group. Compounds 7, 12, 15, and 17 were obtained
through reduction of the aryl nitro group and subsequent
acylation.
Benzimidazoles 1 and 3 and the reduced benzimidazole 4 were
accessed via 2-chloro-5-nitrobenzoyl chloride (Scheme 3), as was
the ring opened amide analog 10. Finally, pyrazolopyridine 6 was
synthesized by cyclization of aminopyridinium iodide with the
acrylate obtained from 2-chloro-5-nitrobenzaldehyde followed by
decarboxylation and rearomatization (Scheme 4).
Following their synthesis, potencies were determined in the Gli
luciferase assay. The clearest trend emerging from the resulting
SAR (Table 1) was a preference for a hydrogen bond acceptor to
be adjacent to the ring junction. When the benzimidazole in 1
was replaced with the isosteric indole in compound 2, which lacks
a hydrogen bond acceptor, potency dropped more than 40-fold. At
the same time, methylation of the benzimidazole nitrogen to re-
move a hydrogen bond donor adjacent to the ring junction in com-
pound 3 did not affect potency significantly. Other potent bicycles
which follow this SAR trend include thiazole 5 and quinoxaline 20.
Additionally, amide 10 can be seen as following this same trend
with the carbonyl oxygen serving as the hydrogen bond acceptor.
Both indazole 7 and pyrazolopyridine 6 are less potent than the
isosteric benzimidazole 1 likely due to the reduced basicity of the
key nitrogen adjacent to the ring. pKa values for this nitrogen in 6
and 7 were calculated to be À0.28 and À0.79, respectively, while
against 2C9 (IC50 = 2.5 lM) and 4.3–6-fold higher in vivo clearance
in rat compared to 15 and 1. Of our most potent heterocycles, we
chose compound 15 as a starting point due to its superior PK in
dog compared to 1 (Table 3). Additionally the predicted clearance
of 15 was lower than that of indazole 7 and quinoxaline 20 in
the preclinical species examined and tracked with in vivo clear-
ance. Quinoxoline 20 also exhibited improved PK in dog versus 1
but had poor solubility.
After examining a wide variety of amide substituents, several
broad themes emerged (Table 2). It appears beneficial to have a
lipophilic substituent in the 2-position of the ring such as a chloro
or methyl substituent as in compounds 15, 21, and 26. The Cl/Me
groups may be making a hydrophobic contact with the protein or
forcing the aromatic ring out of plane with the amide bond.19 Mov-
ing the chloro atom to other ring positions decreased the potency
as evidenced in amides 27 and 28 when compared to the amide 26.
Scheme 1. Reagents and conditions: (a) HNO3, H2SO4; (b) Fe, HOAc; (c) 2-methyl-6-trifluoromethyl-3-nicotinic acid, EDC, 6-Cl HOBt, DIPEA, DMF or 2-methyl-6-
trifluoromethyl-3-nicotinoyl chloride, CH2Cl2, DIPEA, 0 °C, 2 h; (d) Br2, HBr/AcOH, benzene, 0 °C; (e) acetone, 2-methylpyridine, K2CO3; (f) 2-aminothiazole, EtOH; (g) 48% HBr,
DMSO; (h) ethylene diamine, MnO2, C6H6, reflux; (i) phenylenediamine, NaOAc, EtOH, air.

K. D. Robarge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5576–5581
5579
Scheme 2. Reagents and conditions: (a) HCl, NaNO2, then SnCl2; (b) malonaldehyde bis(diethyl acetal), EtOH; (c) 2-nitrobenzaldehyde, POEt3; (d) Fe, HOAc, 80 °C, 0.5 h or
SnCl2, EtOH, concd HCl; (e) 2-methyl-6-trifluoromethyl-3-nicotinoyl chloride, CH2Cl2, DIPEA, 0 °C, 2 h; (f) NaNO2; KI (g) 2-pyridyl zinc iodide in THF, Pd(PPh3)4, TFP, CuI, DMA;
(h) 3-pyridyl boronic acid pinacol ester, Pd(PPh3)4, K2CO3, 4:1 Tol/EtOH, 0.15 h microwave; (i) pinacol diborane, PdCl2(dppf), DMF, 130 °C, 0.4 h microwave; (j) 2-
bromopyrimidine, Pd(PPh3)4, K2CO3, 4:1 Tol/EtOH, 160 °C, 0.2 h microwave; (k) 4-pyridyl boronic acid pinacol ester, Pd(PPh3)4, K2CO3, 4:1 Tol/EtOH, 160 °C, 0.2 h microwave.
Scheme 3. Reagents and conditions: (a) toluene, H2NMe, 2.0 M in THF, 0 °C, 1.5 h; (b) SOCl2, neat, reflux 1.5 h; (c) N-Me carboxyimidazole chloride, THF, TEA, cyclohexanone
oxime, THF, À70 °C to rt;17 (d) p-toluenesulfonic acid, toluene, Dean Stark, reflux 2 d; (e) Fe, HOAc, 80 °C, 0.5 h; (f) DIPEA, CH2Cl2, 2-methyl-6-trifluoromethyl-3-nicotinoyl
chloride, 0 °C, 2 h; (g) DIPEA, CH2Cl2; (h) 2-nitroaniline, pyridine, CH2Cl2; (i) zinc, acetic acid; ethylene glycol, KOH; (j) MeI, acetone, NaOH.
Scheme 4. Reagents and conditions: (a) (ethoxycarbonylmethylidene) triphenylphosphorane, toluene, 50 °C; (b) Fe, AcOH, EtOH; (c) benzoyl chloride, Et3N, CH2Cl2;
(d) 1-aminopyridinium iodide, K2CO3, DMF 40 °C (e) H2SO4, H2O; (f) 2-methyl-6-trifluoromethyl-3-nicotinoyl chloride, CH2Cl2, DIPEA, 0 °C, 2 h.

5580
K. D. Robarge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5576–5581
Table 2
The aromatic nitrogen in 15 appears to play almost no role in its
SAR exploring amide group substituents
potency. Picolinic amide 22 displayed reduced potency relative to
25, while the nicotinic and isonicotinic amides 23 and 24 were
essentially equipotent with 25. We speculate that having a nitro-
gen in the 2-position may reduce potency by enforcing coplanarity
between the amide and aryl ring through an internal hydrogen
bond. The presence of a sulfonyl group in the 3- or 4-position
had a positive effect on binding as demonstrated by 29 and 30,
with the 4-position preferred.
Having optimized the potency and metabolic stability, solubil-
ity became our primary concern. Methylsulfone 30 was equipotent
with nicotinic amide 15 and possesses a lower cLog P but did not
improve the solubility at pH 6.5 (Table 3). At this point, an o-chloro
group, added to enhance potency, was found to significantly im-
prove the solubility at neutral pH. The nearly 20-fold improvement
from 30 to 31 occurs despite a predicted increase in clog P, and
may reflect the reduced planarity of the aryl amide. This does
not however result in a decreased melting point for 31 (264 °C)
as it was measured to be very similar to 30 (251 °C, both measured
as crystalline HCl salts).
The resulting compound 31 (GDC-0449) exhibited improved
potency, solubility and metabolic stability relative to 15 or 30 (Ta-
ble 3). This compound was also potent (2.8 nM) in an analogous
human Gli luciferase assay using human embryonic palatial mes-
enchyme (HEPM) cells.
Compounds 15, 30, and 31 possess excellent potency and low
clearance in both rats and dogs. Low clearance combined with high
absorption translated to high oral exposures.20 Compounds 15 and
31 also demonstrated improved solubility at pH 6.5 relative to oth-
ers in this series. To further characterize these compounds, a PK/PD
study was performed using the Hh responsive tumor cell line
CALU-6 in nude mice.
Cl
N
O
N
R
H
Entry
R
Gli LUC S12 IC50
0.042
(lM)
Me
15
N
CF3
Me
Me
21
22
23
24
0.130
3.000
0.600
0.700
N
N
N
N
The CALU-6 cell line is known to recruit a large stromal compo-
nent, where Hh signaling appears to be operative in tumorigene-
sis.21 Nude mice implanted with human CALU-6 cells were orally
dosed with 75 mg/kg BID of compound 15, 30, or 31 for 3 days to
allow complete suppression of Hh signaling to develop. Following
the final dose, the amount of Gli transcription in the stroma was
determined with mouse specific primers and correlated with expo-
sure (Fig. 2). The nicotinic amide 15 was unable to achieve high en-
ough exposure to see a significant amount of knock down at 4 h
post fifth dose, possibly due to solubility limited absorption at this
higher dose. The unsubstituted methyl sulfone 30 fared slightly
better but displayed a large degree of variability from animal to
animal, again possibly due to poor solubility. The more soluble
chloromethysulfone 31 exhibited a greater than 10-fold knock-
down of Gli suppression versus control and reduced variability.
We attribute the greater degree of Gli suppression to higher plas-
ma concentrations, increased potency and a higher free fraction
(9% free vs 3% (30).
Compound 31 was explored further in a Hh pathway dependent
medulloblastoma allograft model generated from Ptch+/À mice22
and produced complete regression at doses as low as 12.5 mg/kg
BID (Fig. 3). In addition to the mutation-driven autocrine signaling
medulloblastoma model, Hh antagonists have been shown to delay
growth in primary human tumor xenograft models.21
Having started from the potent lead compound 1, we investi-
gated a diverse set of heterocyclic replacements for the benzimid-
azole. This led to a potent series of 2-pyridyl biaryls, which were
further optimized for potency, metabolic stability, PK, and drug-
like properties by incorporating the p-methyl sulfone and o-chloro
functionalities in the amide portion of the molecule. This resulted
in the discovery of Hh antagonist 31, which has progressed into hu-
man clinical trials, where it is being initially evaluated in the treat-
ment of BCC. Since the initiation of GDC-0449 clinical trials, other
Hh pathway inhibitors have entered early stage clinical testing and
25
26
27
28
29
30
31
0.800
0.110
1.500
1.500
0.120
0.040
0.013
Cl
Cl
Cl
SO2Me
SO2Me
SO2Me
Cl

K. D. Robarge et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5576–5581
5581
Table 3
Pharmacokinetics in preclinical species
Entry
Potency Gli LUC S12 IC50 (nM)
CL (hep) pred. from microsomes (mL/min/kg)
Measured clearance (mL/min/kg)
cLog P
Solubility (
pH 1.0
lg/mL)
Rat
Dog
Human
Rat
Dog
pH 6.5
1
7
20
15
30
31
12
80
52
42
40
13
18.5
32
9.1
5.9
2.8
3.7
22
17
16
10
11
11
9.4
7.6
7.4
0.6
5.9
4.5
3.0
124
NA
7.4
1.9
1.4
0.4
3.9
3.8
4.1
3.7
3.2
4.0
300
NA
0.1
1000
420
>3000
0.3
NA
0.1
1.8
0.5
9.5
99.3
10.7
4.5
1.2
3.7
References and notes
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Figure 3. Ptch +/À medulloblastoma allografts treated orally with GDC-0449
formulated as a suspension in 0.5% methylcellulose, 0.2% Tween-80 (MCT).23
20. Contrary to a recent report, GDC-0449 showed no evidence of Pgp inhibition
several more discovered over the last decade are in pre-clinical
development.24
and had no effect on digoxin transport in MDR1-MDCK cells at 15 lM. GDC-
0449 may have been misidentified as HhAntag691 in this publication (Zhang,
Y.; Laterra, J.; Pomper, M. G. Hedgehog Pathway Inhibitor HhAntag691 Is a
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Acknowledgments
The authors thank Martin Struble and Mengling Wong for
purification of compounds, Vickie Tsui for computational support,
Harvey Wong for transport studies with GDC-0449, and Mike
Reich and the in vivo group for their support of PK and PK/PD
studies.
22. Corcoran, R. B.; Scott, M. P. J. Neuro-Oncology 2001, 53, 307.
23. Mice were dosed twice daily. N = 6 per group. Tumors were serially
transplanted subcutaneously in female CD-1 nude mice. The HCl salt of GDC-
0449 was resuspended in MCT (0.5% methylcellulose, 0.2% Tween-80).
24. Tremblay, M. R.; Nesler, M.; Weatherhead, R.; Castro, C. Expert Opin. Ther.
Patents 2009, 19, 1.