Development of small-molecule probes that selectively kill cells induced to express mutant RAS

Article abstract of DOI:10.1016/j.bmcl.2011.09.047

Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS^G12V followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS^G12V oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.

Full text of DOI:10.1016/j.bmcl.2011.09.047

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1822–1826
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of small-molecule probes that selectively kill cells induced
to express mutant RAS
Michel Weïwer a, Joshua A. Bittker a, Timothy A. Lewis a, Kenichi Shimada b, Wan Seok Yang b,
Lawrence MacPherson a, Sivaraman Dandapani a, Michelle Palmer a, Brent R. Stockwell b,
Stuart L. Schreiber a,c, Benito Munoz a,
⇑
a The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, United States
b Howard Hughes Medical Institute, Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY 10027, United States
c Howard Hughes Medical Institute, Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2011
Revised 12 September 2011
Accepted 14 September 2011
Available online 28 September 2011
Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill
oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against
cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes
of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibro-
blasts expressing HRASG12V followed by a counterscreen of lethal compounds in a series of isogenic cells
lacking the HRASG12V oncogene. This effort led to the identification of two novel molecular probes
(PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4–23-fold
selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in
cancer cells.
Keywords:
RAS oncogene
Synthetic lethal
a-Chloroamide
Ó 2011 Elsevier Ltd. All rights reserved.
Nitroisoxazole
MLPCN probes
Cl
O
CF3
O
The first rat sarcoma (RAS) oncogene was discovered as a genet-
O
H
ic element from the Harvey and Kirsten rat sarcoma viruses with
the ability to immortalize mammalian cells.1–3 Mutated RAS onco-
genes (i.e., HRAS, NRAS, and KRAS) are found in 10–20% of all human
cancers and hence are attractive targets for drug development. De-
spite significant efforts,4 currently there are no drugs directly tar-
geting mutated RAS oncogenes. Thus, several modes of indirect
approaches have emerged for targeting RAS including the use of
synthetic lethality.
N
N
N
O
Me
N
O
Me
N
N
Cl
O
Et
Oncrasin-1
Lanperisone
Erastin
Synthetic lethal screening is a chemical biology approach to
identify small molecules that selectively kill oncogene-expressing
cell lines with the goal of identifying pathways that provide spe-
cific targets against cancer cells. Two distinct approaches have
been investigated for identifying compounds exhibiting RAS syn-
thetic lethality. In the first approach, RNAi screens led to the iden-
tification of RAS synthetic lethal genes such as TBK1, CCNA2, KIF2C,
PLK1, APC/C, CDK4, and STK33.5–9 Disappointingly, small molecules
that target the encoded proteins have not been found to show the
same pattern of synthetic lethality.10 In the second approach, phe-
notypic screens have been used to identify inhibitors that are
selectively lethal to cell lines expressing a RAS oncogene. This ap-
proach necessitates further studies to identify the target, but
IC50 ~ 5 µM
IC50 ~ 4 µM
IC50 ~ 2.5 µM
Cl
MeO2C
N
H
N
Me
N
H
Cl
O
CO2CH2CH2OMe
F
O
CO2Me
RSL3
IC50 ~ 0.1 µM
RSL5
IC50 ~ 10 µM
Figure 1. Previously reported small molecules that are lethal to RAS mutant cell
lines.
⇑
Corresponding author.
E-mail address: bmunoz@broadinstitute.org (B. Munoz).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.047

M. Weïwer et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1822–1826
1823
R2
N
nonetheless is an alternative approach towards identifying small
molecules with novel cellular properties.
O
O
O
R2
a)
R4
+
R4
N
R1
R1
N
H
NH2
R3
-
OH
Using a phenotypic approach, Guo and colleagues identified
oncrasin-1 (Fig. 1), which is selectively toxic to cell lines harboring
a KRAS oncogene and ineffective in HRAS mutant cell lines.11 More
recently, Shaw et al. reported a synthetic lethal screen using mouse
embryonic fibroblast harboring an oncogenic KRASG12D allele and
identified lanperisone (Fig. 1) as the most promising candidate.4
Stockwell and co-workers have identified inhibitors (erastin, RSL3
and RSL5, Fig. 1) that are synthetically lethal with cell lines express-
ing mutant HRAS and KRAS.12,13 In this paper, we describe the dis-
covery and development of novel molecular probes exhibiting RAS
synthetic lethality that could be used to identify new pathways
and targets for the development of novel cancer therapeutics.14
A high-throughput screen using the National Institutes of
Health-Molecular Libraries Small Molecule Repository (NIH-
MLSMR) comprising 303,282 compounds (PubChem AID 1832)
was performed. Hits were triaged based on activities on four cell
lines: BJeLR (expressing HRASG12V), BJeH-LT (isogenic to BJeLR
without HRASG12V), DRD (expressing HRASG12V with alternative
oncogenic constructs), BJeH (immortalized background cell line).15
The hits that emerged from these secondary screens were evalu-
ated for cell viability, which led to the identification of 73 com-
O
R3
Scheme 1. Synthesis of
reaction. Reagent and conditions: (a) MeOH, 23 °C, 48 h.
a-chloroamide analogs using the Ugi 4-component
Table 1
SAR of the aniline portion
R2
R1
O
N
Cl
N
H
O
S
R1
R2
IC50 (lM)
Selectivityb
a
Compd
BJeLR
BJeH-LT
1a
1f
1g
1h
Cl
H
Cl
OMe
OMe
OMe
H
0.025
0.22
0.156
0.17
0.578
1.7
0.331
2.4
23
7.8
2.1
14
H
pounds that had IC50 <2.5
selectivity against the isogenic BJeH-LT cell line. Two hit clusters,
an -chloroacetamide and a nitroisoxazole, were identified and
lM against BJeLR and >4-fold
a
Values are means of experiments performed in triplicate.
b
BJeH-LT IC50/BJeLR IC50
.
a
prioritized for optimization. The structures of lead compounds
(1a and 2a) from the two series are shown in Figure 2 and the
structure/activity relationships (SAR) of these two lead compounds
are the subject of this paper.
Table 2
SAR on the thiophene portion
OMe
N
The first cluster represented by compound 1a features an
a-
Cl
chloroacetamide that can potentially act as an electrophile.
Although covalent inhibitors are rarely considered when initiating
a drug discovery program, they have proved to be successful in var-
ious disease areas.16,17 Particularly, in the context of phenotypic
screens, where the target is unknown, covalent inhibitors can facil-
itate target identification through pull-down experiments. RSL3, a
O
Cl
N
H
R1 R2
O
Compd
R1
R2
IC50 (lM)
Selectivityb
a
BJeLR
BJeH-LT
previously reported RAS synthetic lethal molecule is also an
a-
chloroacetamide with an IC50 of 100 nM in BJeLR and approxi-
mately eightfold selectivity versus BJeH-LT.14 Compound 1a also
1a
H
0.025
0.578
23
S
possesses a
a-chloroamide sub-unit but shows increased activity
and selectivity compared to RSL3 and was thus considered a supe-
rior scaffold for SAR studies. To investigate the SAR of 1a, several
analogs were synthesized using the Ugi 4-component reaction
(Scheme 1). The influence of all four components was investigated,
and the results are presented in Tables 1–3.
1i
1j
H
H
0.505
0.895
1.18
1.3
2.3
1.5
Me
S
Me
Our initial goal was to determine if the
a-chloroamide moiety
N
was essential for activity. Thus, analogs where the chloro func-
tional group of 1a was replaced with a methyl, a methoxy, a hydro-
xyl moiety, and a heterocyclic leaving group18 (1b–e, Fig. 3) were
prepared. All of these analogs were found to be inactive, suggesting
1k
H
8.26
19.8
2.4
Me
S
1l
H
0.061
0.133
2.2
that the
a-chloroamide moiety is required for activity.
Cl
Me
H
1m
1n
Me
H
0.058
0.231
0.127
0.531
2.2
2.3
OMe
a
Cl
Values are means of experiments performed in triplicate.
BJeH-LT IC50/BJeLR IC50
b
.
O
O
N
N
NO2
Me
N
S
Cl
N
H
N
In order to assess the stability of 1a as a nonselective akylating
O
O
agent, it was subjected to the presence of glutathione (GSH). After
48 h of incubation of 1a in PBS/DMSO (1:2) at room temperature,
in the presence of a physiologically relevant amount of GSH
(5 mM), only 20% of the corresponding GSH adduct was observed.
This indicates that 1a is not highly reactive toward thiols and is rel-
atively stable in the presence of nucleophiles such as GSH. When a
1a
2a
IC50 (BJeLR; Mutant) = 0.025 µM
IC50 (BJeH-LT; Wild-type) = 0.578 µM
IC50 (BJeLR; Mutant) = 1.03 µM
IC50 (BJeH-LT; Wild-type) = 4.97 µM
Figure 2. Hit compounds from the high throughput screening campaign.

1824
M. Weïwer et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1822–1826
Table 3
analog 1l was found to be very potent with an IC50 of 61 nM in
SAR of the phenethylamine portion
BJeLR cell line. However, its selectivity was only 2.2-fold. The thio-
phene ring was removed in order to address the presence of a ste-
reogenic center in the molecule. Acetone or formaldehyde was
used in the Ugi reaction in order to generate the gem-dimethyl
moiety (1m) or a methylene moiety (1n), respectively, in place of
the thiophene substituent. The gem-dimethyl analog (1m) was
equipotent to the initial hit (1a) with an IC50 of 58 nM in BJeLR cell
line but lacked the selectivity. Compound 1n showed decrease in
potency and selectivity.
OMe
Cl
O
N
S
R
Cl
N
H
O
Compd
R
IC50
(
lM)
Selectivityb
a
The influence of the phenethylamine portion of the hit com-
pound was investigated by using different isocyanide components
in the Ugi reaction (Table 3). Replacement of the phenethylamine
group by shorter hydrophobic amines (1o–p) afforded potent com-
pound but the selectivity was eroded.
In addition to investigating the SAR, attempts were made to im-
prove the aqueous solubility of 1a by the introduction of a sulfone
group (1q). Although this approach improved the aqueous solubil-
BJeLR
BJeH-LT
1a
0.025
0.578
23
1o
1p
0.113
0.075
0.27
2.4
2.4
0.179
ity (16 lM vs <1 lM) it led to a decrease in activity and a 10-fold
Me
reduction in selectivity. Introduction of a benzotriazole group
(1r) did not improve solubility and also led to a decrease in activity
and selectivity.
1q
1r
0.089
0.102
0.208
0.242
2.3
2.4
S
N
O
O
Compound 1a was found to be the most potent and selective
analog in the series. The
a-chloroamide portion is required for
N
activity, and the 3-chloro-4-methoxyaniline, the thiophene ring
and the phenethylamine portion were found to be optimal for
activity and selectivity. Both activity and selectivity of 1a were
confirmed using another pair of HRAS-mutant and wild-type cell
lines; HRASG12V cell line (DRD, IC50 = 34 nM) and HRAS wild-type
cell line (BJeH, IC50 = 2400 nM).
The SAR of the second cluster, the nitroisoxazole hit 2a (Fig. 2),
was then investigated. The synthesis of the analogs was accom-
plished in six steps using the general scheme developed for the
synthesis of 2a (Scheme 2). Nitration of the 5-methylisoxazole-3-
carboxylic acid 3 was accomplished using concentrated sulfuric
acid and potassium nitrate. The obtained compound 4 was con-
verted to the corresponding acid chloride 5 in quantitative yield.
Benzophenone derivatives 6 were reduced using sodium borohy-
dride to the corresponding alcohol 7. Treatment of 7 with oxalyl
chloride provided 8 and was followed by treatment with an excess
of piperazine in refluxing acetonitrile to afford 9. Coupling of sec-
ondary amines 9 with the acid chloride 5 in dichloromethane
afforded the final compounds 2.
N
a
Values are means of experiments performed in triplicate.
BJeH-LT IC50/BJeLR IC50
b
.
OMe
Cl
R
1a
Cl
O
1b Me
N
S
1c OMe
R
N
H
1d
OH
O
1e 2-thiopyrimidine
Figure 3. SAR on the a-chloroamide portion.
base (triethylamine) was added, the formation of the GSH adduct
was observed in 1 h.
Compound 1a is a racemate and was thus, subjected to chiral
HPLC separation to investigate the importance of the stereogenic
center on activity and selectivity. Both enantiomers were obtained
with >99% ee (see Supplementary data) and were tested in the cell
assays. They were shown to have similar activity and selectivity for
HRASG12V cell lines. To establish whether the enantiomers could
racemize under the assay conditions, each enantiomer was sub-
jected to a PBS stability assay. After 48 h incubation in PBS (0.1%
DMSO), the stereochemical integrity of the compound was as-
sessed by chiral HPLC/MS. No detectable racemization was ob-
served (see Supplementary data). Given these results, all analogs
prepared for SAR studies were synthesized as racemates.
The influence of the substitution on the aniline ring was then
examined (Table 1). Both the meta-chloro substitutent and the
para-methoxy substitutent were found to be critical for activity,
as removal of either one led to a 10-fold decrease in activity (1f–
g). A meta-methoxy (1h) led to a decrease in activity.
Different aldehydes were used in the Ugi reaction to investigate
the SAR at the thiophene position (Table 2). Replacing the thio-
phene ring with hydrophobic group such as a cyclohexyl or an iso-
propyl group (1i–j) led to a decrease in activity and selectivity. The
thiophene was also replaced with a thiazole (1k) or a 2-chlorothio-
phene (1l) in order to deactivate the 3-position. The thiazole ana-
log 1k was shown to be inactive, but the 2-chlorothiophene
O
N
O
N
HO
R
NO2
Me
b)
a)
c)
Me
O
3
O
4
5
R = OH
R = Cl
X
O
R
R
R
R
7
8
X = OH
X = Cl
6
d)
R
R
R
O
e)
f)
N
N
N
NH
NO2
Me
N
9
2
R
O
Scheme 2. Representative synthesis of the nitroisoxazole compounds 2. Reagents
and conditions: (a) H2SO4, KNO3; (b) Oxalyl chloride, CH2Cl2; (c) NaBH4, THF–MeOH
1:1; (d) oxalyl chloride, CH2Cl2; (e) piperazine, CH3CN; (f) 5, CH2Cl2.

M. Weïwer et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1822–1826
1825
Even though the nitro group is present in several FDA—ap-
proved drugs, it can be a liability in many instances.16 Thus, an at-
tempt was made to replace the nitro group with other functional
groups (Fig. 4).
Replacement of the nitro group by a primary amine, acetamide,
sulfonamide, bromine, methyl, and hydrogen (2b–g, Fig. 3) led to
inactive compounds, suggesting the importance of the nitro group
for activity.
The influence of the nitroisoxazole ring on the activity of the
compound (Table 4) was addressed. Replacing the nitroisoxazole
ring with other nitroaromatics, such as 4-nitropyrazole (2h–j),
led to inactive compounds. A nitropyridyl analog (2k) was found
to be a weak inhibitor and demonstrated poor selectivity. Nitro-
phenyl (2l), as well as a nitrofuran analog (2m) were also found
to be inactive. Thus, the nitroisoxazole moiety of the molecule
was found to be important for activity and was conserved intact
for further SAR studies.
piperazine portion with morpholine (2n) or a shorter amide like
the p-fluorobenzyl analog (2o) provided inactive compounds.
Keeping the piperazine ring in place and only replacing the benz-
hydryl portion with an ethylcarbamate (2p) or an o-methoxy-
phenyl ring (2q) also led to inactive compounds. Even the
removal of one of the two phenyl rings of 2a (2r) was sufficient
to eliminate activity demonstrating that the benzhydryl portion
is necessary for activity. Replacing the piperazine linker with
homopiperazine (2s) led to a modest improvement in activity but
also resulted in a modest decrease in selectivity. Hence, suggesting
that homopiperazine is tolerated at that position. The ethylene dia-
mine analog (2t) afforded a dramatic decrease in activity indicating
the importance of rigidity in this quadrant as well as the impor-
tance of hydrogen bonding acceptors.
To improve activity and solubility of the lead, the substitution
on both phenyl ring of the benzhydryl group was studied (Table
6). Replacement of both phenyl groups by 2-pyridyl (2u) or 4-
pyridyl groups (2v) increased aqueous solubility to afford analogs
The influence of the benzhydryl-piperazine portion of the mol-
ecule was then investigated (Table 5). Replacing the benzhydryl-
with solubility greater than 500 lM. Unfortunately, both of these
compounds were found to be inactive.
Introducing p-fluoro substituents on both phenyl rings (2w) led
to a fivefold increase in activity with a slight decrease in selectivity.
Introduction of p-methoxy substituents on both phenyl groups
(2x) led to a decrease in activity and selectivity. The introduction
of p-chloro substituents on both phenyl rings (2y) led to a 14-fold
increase in activity at the cost of a slight decrease in selectivity.
Taking clues from the structure of the drug cetirizine, we made
an analog that contains an unsymmetrical benzhydryl unit where
only one phenyl ring has a 4-chloro substituent (2z). Unfortu-
nately, this modification led to a decrease in activity. The amide
function of 2y was also reduced to the corresponding amine (2y0,
see Supplementary data), which led to a decrease in activity
R
2a NO2
2b NH2
2c NHAc
2d NHSO2Me
2e Br
2f Me
2g H
O
N
N
R
N
Me
O
Figure 4. SAR at the 4-position of the nitroisoxazole ring.
Table 4
SAR on the nitroisoxazole portion
O
R
Table 5
N
N
SAR on the benzhydrylpiperazine portion
O
R
NO2
Me
IC50
a
Compd
R
IC50
(
l
M)
Selectivityb
N
O
BJeLR
BJeH-LT
a
Compd
R
(
l
M)
Selectivityb
4.8
NO2
Me
BJeLR
BJeH-LT
2a
2h
1.03
IA
4.97
IA
4.8
N
N
O
Ph
Ph
O
NO2
N
N
2a
1.03
4.97
NAc
NAc
NA
N
H
N
2n
2o
IA
IA
IA
IA
NO2
F
HN
N
N
2i
IA
IA
NA
N
Me
O
N
2p
IA
IA
NA
EtO
NO2
2j
IA
IA
NA
N
N
N
Me
2q
2r
2s
IA
IA
NA
NA
3.6
N
OMe
N
NO2
Ph
Ph
2k
37.3
49.7
1.33
IA
IA
N
N
NO2
O
N
N
2l
IA
IA
IA
NA
NA
0.773
2.79
Ph
Ph
Me
NH HN
2t
21.6
IA
NA
2m
18.9
NO2
Ph
a
b
c
a
b
c
Values are means of experiments performed in triplicate.
BJeH-LT IC50/BJeLR IC50
IA = Inactive, highest concentration tested was 20
Values are means of experiments performed in triplicate.
BJeH-LT IC50/BJeLR IC50
IA = Inactive, highest concentration tested was 20
.
.
lg/ml. NA = Not applicable.
l
g/ml. NA = Not applicable.

1826
M. Weïwer et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1822–1826
Table 6
Acknowledgments
SAR on the benzhydryl portion
R1
R2
O
This work was funded by the NIH-MLPCN program (1 U54
N
N
NO2
Me
HG005032-1 awarded to S.L.S.) and (R01CA097061 and
R03MH084117 awarded to B.R.S.). S.L.S. and B.R.S. are Investigators
with the Howard Hughes Medical Institute.
N
O
R1, R2
IC50 (lM)
Selectivityb
a
Compd
Supplementary data
BJeLR
BJeH-LT
2a
2u
2v
2w
2x
2y
2z
R1 = R2 = Ph
1.03
IA
IA
0.183
1.57
0.071
0.129
4.97
IA
IA
0.757
5.32
0.272
0.51
4.8
NAc
NA
4.1
3.4
3.9
4.0
Supplementary (protocols for the synthesis of analogs and bio-
assays, 1H and 13C NMR and LC–MS) data associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.bmcl.2011.09.047.
R1 = R2 = 2-Pyridyl
R1 = R2 = 4-Pyridyl
R1 = R2 = 4-F-Ph
R
1 = R2 = 4-OMe-Ph
R1 = R2 = 4-Cl-Ph
R1 = Ph, R2 = 4-Cl-Ph
References and notes
a
b
c
Values are means of experiments performed in triplicate.
BJeH-LT IC50/BJeLR IC50
IA = Inactive, highest concentration tested was 20
1. Harvey, J. J. Nature 1964, 204, 1104.
2. Kirsten, W. H.; Mayer, L. A. J. Natl. Cancer Inst. 1967, 39(2), 311.
3. Barbacid, M. Annu. Rev. Biochem. 1987, 56, 779.
.
lg/ml. NA = Not applicable.
4. Shaw, A. T.; Winslow, M. M.; Magendantz, M.; Ouyang, C.; Dowdle, J.;
Subramanian, A.; Lewis, T. A.; Maglathin, R. L.; Tolliday, N.; Jacks, T. Proc.
Natl. Acad. Sci. U.S.A. 2011, 108, 8773.
(26.4 l
M in BJeLR). Homologation of 4 to produce 2w0 was also
accomplished (see Supplementary data) but led to a less potent
5. Mizuarai, S.; Kotani, H. Hum. Genet. 2010, 128, 567.
6. Luo, J.; Emanuele, M. J.; Li, D.; Creighton, C. J.; Schlabach, M. R.; Westbrook, T.
F.; Wong, K. K.; Elledge, S. J. Cell 2009, 137, 835.
7. Puyol, M.; Martın, A.; Dubus, P.; Mulero, F.; Pizcueta, P.; Khan, G.; Guerra, C.;
Santamarıa, D.; Barbacid, M. Cancer Cell 2010, 18, 63.
compound (2.99 M in BJeLR).
l
Overall, studying the effect of structural changes of the
benzhydryl portion of the molecule on activity turned out to be
productive, and led to the identification of 2y with the bis-4-chlo-
rophenyl substituent as the most potent compound in the nitrois-
oxazole series. Compound 2y was also found to have an IC50 of
107 nM in the DRD cell line, which represents a 16-fold increase
in activity compared to the hit compound 2a. It also shows an
IC50 of 628 nM in the BJeH cell line. This represents a sixfold selec-
tivity for the DRD (HRASG12V) versus the BJeH (non expressing
HRASG12V) cell line.
In conclusion, HTS of the MLPCN library followed by SAR inves-
tigation led to the identification of two HRAS synthetic lethal com-
pounds 1a and 2y with nanomolar potencies against two HRASG12V
expressing cell lines and 4–23-fold selectivities against two control
cell lines not expressing HRASG12V. Because these two probes were
identified through a phenotypic screen, their target is still un-
known. Future studies will be initiated in order to understand their
mode of action and to shed light on RAS-dependent cancers. Com-
pounds 1a and 2y have been registered with NIH Molecular
Libraries Program (ML 162 and ML 210, respectively) and are avail-
able upon request.
8. Scholl, C.; Frohling, S.; Dunn, I. F.; Schinzel, A. C.; Barbie, D. A.; Kim, S. Y.; Silver,
S. J.; Tamayo, P.; Wadlow, R. C.; Ramaswamy, S., et al Cell 2009, 137, 821.
9. Barbie, D. A.; Tamayo, P.; Boehm, J. S.; Kim, S. Y.; Moody, S. E.; Dunn, I. F.;
Schinzel, A. C.; Sandy, P.; Meylan, E.; Scholl, C., et al Nature 2009, 462, 108.
10. Babij, C.; Zhang, Y.; Kurzeja, R. J.; Munzli, A.; Shehabeldin, A.; Fernando, M.;
Quon, K.; Kassner, P. D.; Ruefli-Brasse, A. A.; Watson, V. J.; Fajardo, F.; Jackson,
A.; Zondlo, J.; Sun, Y.; Ellison, A. R.; Plewa C. A.; San Miguel, T.; Robinson, J.;
McCarter, J.; Schwandner, R.; Judd, T.; Carnahan, J.; Dussault, I. Cancer Res.
doi:10.1158/0008-5472.CAN-11-0778.
11. Guo, W.; Wu, S.; Liu, J.; Fang, B. Cancer Res. 2008, 68, 7403.
12. Dolma, S.; Lessnick, S. L.; Hanh, W. C.; Stockwell, B. R. Cancer Cell 2003, 3, 285.
13. Yang, W. S.; Stockwell, B. R. Chem. Biol. 2008, 15, 234.
14. Chan, D. A.; Giaccia, A. J. Nat. Rev. Drug Disc. 2011, 10, 351.
15. Hahn, W. C.; Counter, C. M.; Lundberg, A. S.; Beijersbergen, R. L.; Brooks, M. W.;
Weinberg, R. A. Nature 1999, 400, 464.
16. Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. Nat. Rev. Drug Disc. 2011, 10, 307.
17. Perez, D. I.; Palomo, V.; Perez, C.; Gil, C.; Dans, P. D.; Luque, F. J.; Conde, S.;
Martinez, A. J. Med. Chem. 2011, 54, 4042.
18. Lepore, S. D.; Mondal, D. Tetrahedron 2007, 63, 5103.