Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity

Article abstract of DOI:10.1016/j.bmcl.2011.03.112

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.

Full text of DOI:10.1016/j.bmcl.2011.03.112

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3411–3416
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Macrocyclic lactams as potent Hsp90 inhibitors with excellent
tumor exposure and extended biomarker activity
Christoph W. Zapf a, , Jonathan D. Bloom a, Jamie L. McBean a, Russell G. Dushin a, Thomas Nittoli a,
⇑
Mercy Otteng a, Charles Ingalls a, Jennifer M. Golas b, Hao Liu b, Judy Lucas b, Frank Boschelli b,
Yongbo Hu c, Erik Vogan d, Jeremy I. Levin a
a Medicinal Chemistry, 401 N Middletown Road, Pearl River, NY 10965, United States
b Oncology Research, 401 N Middletown Road, Pearl River, NY 10965, United States
c Structural Biology Computational Chemistry, Pfizer, 401 N Middletown Road, Pearl River, NY 10965, United States
d Structural Biology Computational Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02139, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our
research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities.
This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and
efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged
Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged expo-
sure in the tumor.
Received 3 March 2011
Revised 25 March 2011
Accepted 29 March 2011
Available online 5 April 2011
Keywords:
Hsp90 inhibitors
Ó 2011 Elsevier Ltd. All rights reserved.
Ortho-aminobenzamides
Tumor exposure
Macrocycles
Buchwald–Hartwig cyclization
Modern cancer chemotherapy generally suffers from the emer-
gence of drug resistance.1,2 The selective silencing of a specific cell
signaling pathway by a chemotherapeutic is arguably at the origin
of this problem. By up-regulating alternative pathways, tumors are
able to adapt to the drug treatment and continue their growth.
Targeting chaperone proteins offers a promising solution to this
traditional chemotherapy dilemma, since it allows the simulta-
neous inhibition of multiple pathways with a single agent.3,4
The ATP-dependent 90 kDa molecular chaperone Hsp90 has be-
come an attractive target for cancer therapy.5,6 It plays a critical
role in maintaining the function of a wide range of client proteins,
many of which are intimately involved in cancer pathology.7 Inhi-
bition of Hsp90 leads to the destabilization, and ultimately the
degradation of the clients, which results in the inhibition of cell
growth and apoptosis.8
The first Hsp90 inhibitor reported in the literature was the mac-
rocyclic natural product Geldanamycin 1 (Fig. 1), which belongs to
the class of the ansamycins.13 Clinical studies established this com-
pound’s unacceptable toxicology profile, preventing it from further
development.14 Optimization studies led to the discovery of 17-
AAG 2 and 17-DMAG 315 which are currently in clinical trials,
but are characterized by poor solubility and a narrow therapeutic
window, respectively.
Vernalis recently disclosed resorcinol 416 which entered clinical
trials in 2007. Isoxazole 4 is one of many small molecules which
have been described in the literature as potential novel Hsp90
inhibitors with clinical application and is part of a recent summary
on this topic.17
Serenex recently disclosed their own efforts to discover potent
small-molecule Hsp90 inhibitors that would be devoid of the
drawbacks associated with Geldanamycin.18 Their studies culmi-
nated in a series of 2-aminobenzamides which exhibited low-
nanomolar potencies in a proliferation assay. Among the reported
compounds, glycine pro-drug SNX-5422 5 was forwarded to clini-
cal trials.19
In continuation of seeking potent small molecule inhibitors of
Hsp90, and guided by X-ray crystallography using a structural
analog of 5, we were able to design and synthesize macrocyclic
ortho-aminobenzamides. We recently disclosed a new series of
Different ATP-competitive chemotypes have evolved as potent
N-terminal Hsp90 inhibitors, several of which have transitioned
into clinical trials.9–11 While many of these clinical trials focus on
Hsp90 inhibitors as single agents for cancer therapy, combination
studies with established chemotherapeutics have been designed
and were reported recently as well.12
⇑
Corresponding author. Tel.: +1 617 665 5602; fax: +1 617 665 5682.
E-mail addresses: chzapf@gmail.com, christoph.zapf@pfizer.com (C.W. Zapf).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.03.112

3412
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3411–3416
O
O
CONH2
R
O
H
O
N
N
O
N
H
NH2
O
HO
N
MeO
N
OH
O
MeO
CF3
OH
O
N
HN
OCONH2
O
1 Geldanamycin: R = OMe
2 17-AAG: R = NHallyl
4 NVP-AUY922
5 SNX-5422
3 17-DMAG: R = NHCH2CH2NMe2
Figure 1. Structure of Geldanamycin 1, clinically relevant ansamycins 17-AAG 2, 17-DMAG 3, Vernalis’ clinical candidate NVP-AUY922 4 and Serenex’ clinical candidate SNX-
5422 5.
CONH2
CONH2
CONH2
H
H
H
Me
NH
Me
N
N
N
N
Me
NH
N
N
N
Me
O
O
O
O
8
6
7
CONH2
CONH2
CONH2
H
H
H
N
N
N
R
O
N
N
R
O
N
N
N
N
O
R
O
O
O
9
10
11
Figure 2. Previously reported macrocycles20 and structures 8–11 discussed below.
macrocycles several of which are potent inhibitors of Hsp90 in an
enzyme and a HCT116 cell-proliferation assay.20 Beside its po-
tency, analog 6 (Fig. 2) has acceptable solubility and rat micro-
somal stability. Compound 7, which is devoid of the basic amine
functionality, was found to be similarly potent but displayed poor
stability in rat microsomes. Further investigations into the compo-
sition of the macrocyclic linker led to the discovery of amine 8
which is potent in the enzyme and cell-based assays (Table 1).
Unfortunately, but not surprisingly, with its basic amine the com-
Buchwald cyclization and hydrolysis yielded the desired target
macrocycles 27–33.
Employing similar chemistry, a related series of analogs was
prepared in which the amide had been moved within the tether
(Scheme 3). The respective amines 36 were accessed from the
homo-allyl tetrahydroindolone 34 through the same sequence of
dihydroxylation and cleavage followed by appropriate conversion
to the desired primary or secondary amines as indicated. Acyla-
tions using the required protected alanine or (S)-homo-alanine
was again followed by deprotection, cyclization and hydrolysis to
produce analogs 38–43.
pound is
(IC50 = 3.2
a
potent inhibitor of the hERG ion channel
l
M).21 This manuscript details a series of macrocyclic
amides 9 and lactams 10–11 (Fig. 2) which were designed to mit-
igate hERG activity.
Macrocycle 6, reported previously, is a potent inhibitor of
Hsp90 enzyme in the fluorescence-polarization binding assay22, a
cell-based vSrc assay23 and a cell proliferation assay (Table 1). Re-
lated analog 8 is even more potent in all three assays but also a po-
Previously reported macrocyclic amine 6 was elaborated to pro-
duce the exocyclic amides 12–17 (Scheme 1). Likewise, analogs
18–21 were obtained from the corresponding amine through stan-
dard amide formation chemistry.
The synthesis of a series of lactams is depicted in Scheme 2.
The allyl-substituted tetrahydroindolone derivative 22 was ad-
vanced to the carboxylic acid derivative 24 following dihydroxy-
lation, diol cleavage and oxidation under standard conditions.
Amide formation utilizing different readily prepared Boc-pro-
tected amines 25 and subsequent deprotection, followed by
tent hERG inhibitor (IC50 = 3.2 lM). We therefore sought
macrocycles devoid of hERG activity. Analog 7 was used as a start-
ing point since the hERG activity was attributed to the presence of
the basic amine. Analog 7 was not quite as potent as 8, which led to
the design and preparation of amides 12–17. While the enzyme po-
tency suffered only slightly, the compounds behaved poorly in the
cell-based assays. However, rat microsomal stability and solubility
in most cases remained in the desired range.

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3411–3416
3413
Table 1
modeling suggested that the chemical nature of the tether can
have a profound influence on the overall conformation of the mac-
rocycle and thus on its biological activity.
Biological activities, profiling data, and selected calculated properties for macrocycles
6–43. For experimental details regarding assay conditions see ref.22
#
Hsp90a vSrcb
HCT116c Ratd Sol.e
MWf TPSAg clogPh
Our next efforts focused on the preparation and evaluation of
macrocyclic lactams 27–33. The initial hypothesis was to test
whether the amide itself would rigidify the unsubstituted tether
sufficiently, rendering the stereocenter obsolete. However, a com-
parison of 27 and 28 quickly established that the incorporation of
this methyl substitutent had again a dramatically positive effect on
the potency of the macrocycle. Replacement of the amide NH with
NMe (29) was beneficial, which led to the preparation of analogs
30–33. Incorporation of larger amide substitutents, however, led
to a reduction in potency.
Simultaneously to these efforts, the synthesis of lactams was
carried out in which the amide group had been reversed and
moved by one position along the tether toward the carboxamide.
The first analog prepared in this series (38) is about equipotent
to amine 8 in all three assays. This analog retains biological activity
and physical properties while improving the calculated properties
such as TPSA and clogP. Moreover, the compound shows only
6
7
8
0.11
0.111
0.091
0.116
0.108
0.047
0.917
6.183
0.488
0.238
0.674
0.109
0.111
1.159
>5
0.093
0.151
0.043
1.009
4.894
0.71
>30
9
>30
NT
>30
>30
>30
>30
3
11
12
>30
>30
NT
>100 409
19 451
>100 409
NT 466
>100 480
>100 480
>100 480
89
97
89
123
123
123
123
127
101
97
4.1
2.8
4.1
2.6
2.8
2.9
2.9
2.6
3.6
3.4
3.4
4.1
3.5
1.9
2.5
2.9
3.7
3.4
3.5
2.4
3.5
3.5
3.9
3.6
3.5
3.4
12 0.09
13 0.2
14 0.119
15 0.145
16 0.14
17 0.14
18 0.219
19 0.953
20 >5
21 0.555
27 6.831
28 0.214
29 0.156
30 0.608
31 0.222
32 0.191
33 0.407
38 0.082
39 0.268
40 0.092
41 1.181
42 0.24
43 0.337
0.314
1.55
5
508
>100 494
69 451
0.168
0.194
1.897
3.263
>5
>100 451
>100 494
>100 480
97
101
123
106
106
97
>5
NT
NT
NT
409
0.522
0.16
0.278
0.108
0.249
>5
0.079
0.123
0.06
0.815
0.247
0.865
0.359
0.33
>30
>30
12
>30
>30
>30
>30
NT
>30
NT
>30
NT
>100 423
>100 437
>100 465
>100 481
>100 494
>100 508
>100 423
97
107
101
127
106
106
97
123
127
106
>5
about a 7% inhibition of the hERG channel at 11
>33 M), a substantial improvement over amine 8, which inhibits
hERG with 78% at the same concentration (IC50 = 3.2
M).21 Inver-
lM (IC50
0.056
0.175
0.08
l
NT
34
423
437
l
>20
>20
>100 466
>100 508
NT
sion of the chirality (39) leads to a loss in potency while amide
methylation (40) does not influence the excellent potency as ex-
pected when comparing 28 and 29. Likewise, the incorporation of
larger amide substituents (41 and 42) leads to an erosion of
activity. To confirm our previous findings regarding ring-size, we
prepared 43 in which the macrocycle is increased from a 12-mem-
bered to a 13-membered ring. As before, a consistent reduction in
activity for this analog was observed.
The results in Table 1 showed consistent SAR trends and the
cell-based vSrc data correlates well with the cell-proliferation data
(Fig. 3). Activity was generally maintained or improved compared
to the previously reported compounds20 while rat microsomal sta-
bility and solubility were retained. These results prompted us to
further characterize 38.
15.771 17.897
1.842 3.33
437
a
b
c
Enzyme IC50 [lM].
Cell-based functional assay.
Cell-proliferation EC50 M].
t1/2 in rat microsomes [min].
Solubility [ g/mL].
Molecular weight.
Total polar surface area;
Calculated partition ratio.
[
l
d
e
f
l
g
h
We next decided to prepare acylated analogs of 6 and 8 which
led to the synthesis of compounds 18–21. While the physical prop-
erties of these compounds were mostly acceptable, their potency
was generally reduced. This result was unexpected since this
portion of the macrocyclic tether was thought to point toward
the solvent exposed region of the enzyme.20 However, molecular
An X-ray crystal structure of 40, the N-methyl analog of 38,
bound to the N-terminal ATP-binding site of Hsp90 was obtained.24
This substrate was chosen for the crystallographic studies since it
contains an N-methyl substituent which was expected to provide
CONH2
H
(Boc-protected)
amino acid
Me
N
12: R = CH2NH2
13: R = CH2CH2NH2
14: R = (R)CH(CH3)NH2
15: R = (S)CH(CH3)NH2
16: R = CH2NHCOCH3
17: R = CH2N(CH3)2
a
6
N
N
R
(b)
O
O
CONH2
H
CONH2
H
Me
N
N
O
19: R = Me
NAc
Me
N
R
20: R = CH2N(CH3)2
21: R = (R)CH(CH3)NH2
N
N
O
O
18
Scheme 1. Novel exocyclic amides 12–21. (a) EDC, HOBt, Et3N, DCM; (b) 10% TFA in DCM (if Boc-protecting group needed to be removed).

3414
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3411–3416
CN
N
CN
Br
CN
N
Br
Br
a
b,c
N
COOH
OH
HO
O
O
O
22
23
24
R
X
BocHN
N
d,e
H
25
CONH2
CN
H
#
R
X
R
Br
N
R
NH2
27
H
H
H
Me
28 Me
29 Me
30 Me
f,g
N
N
N
iPr
X
31 Me CH2CH2OMe
N
X
O
32
33
Me CH2CH2NMe2
Me CH2CH2NAc
O
O
O
27 - 33
26
Scheme 2. (a) OsO4, NMO, tBuOH, 70%; (b) NaIO4/SiO2, DCM, quant.; (c) NaClO2, NaH2PO4ÁH2O, 2-methyl-2-butene, tert-BuOH, H2O, 96%; (d) EDC, HOBt, Et3N, DCM, 47–95%;
(e) 10% TFA, DCM, quant.; (f) Pd2dba3, BINAP, NaOtBu, dioxane, toluene, 110 °C, 45–98%; (g) 5 M NaOH, 30% H2O2, DMSO, EtOH, 44–78%.
CN
N
CN
CN
Br
Br
Br
a,b
c,d,e,f
N
N
CHO
or c,d,g
or c,d,h
NH
O
O
O
34
35
36
R
R'
R''
BocHN
i,j
COOH
n
CONH2
CONH2
CN
N
H
H
R''
R''
R'
Br
N
N
R'
H2N
R
R
n
O
k,l
NH
O
N
or
N
O
N
N
O
O
O
43
38 - 42
37
#
R'
R''
R
#
R'
R''
R
38
39
40
41
42
Me
Me
H
H
(CH2)2NH2
(CH2)2NHAc
Me
H
Me
H
Me
H
H
H
Me
m
Scheme 3. (a) OsO4, NMO, tBuOH, 70%; (b) NaIO4/SiO2, DCM, quant.; (c) NaBH4, THF, 0 °C, 71%; (d) MeSO2Cl, Et3N, DCM; (e) NaN3, DMF; (f) PPh3, H2O; (g) MeNH2; (h)
BocNHCH2CH2NH2; (i) EDC, HOBt, Et3N, DCM, 47–95%; (j) 10% TFA, DCM, quant.; (k) Pd2dba3, BINAP, NaOtBu, dioxane, toluene, 110 °C; (l) 5 M NaOH, 30% H2O2, DMSO, EtOH;
(m) Ac2O.

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3411–3416
3415
Figure 5. Biomarker effects of 38 at 50 mg/kg PO. Each vertical lane with its five
markers represents data from an individual animal.
Table 3
Exposure levels of 38 after 50 mg/kg PO dosing
6 h
24 h
Plasma
Tumor
146 ng/mL
2129 ng/g
8 ng/mL
1266 ng/g
Figure 3. vSrc activity correlates with proliferation activity.
ATP inhibitors. However, a substantial conformational difference
can be noted when comparing the binding conformation of ATP
in the active site of Hsp90 with its conformation in kinases. Com-
pound 38 was tested against the Invitrogen panel of 59 kinases and
was found to inhibit these kinases with an IC50>50 lM.
Further characterization of 38 in other cell lines revealed a
broad spectrum of remarkable activity across various cell lines
including melanoma (A375, WM266-4), lung (A549, NCI-1975),
breast (BT474, MDAMB361), prostate (DU145), colon (HCT116)
and glioblastoma (T98G, U87MG) cells (Table 2). The compound
also showed activity in KB cells and MDR cells (KB8.5) but was
inactive in cells expressing high levels of P-gp transporters (KBV1).
We next studied 38 in a biomarker efficacy study in a xenograft
model using MDA-MB-361 tumors (Fig. 5). When administered at
50 mg/kg PO, the compound clearly elicits a heat-shock response
characterized by an up-regulation of Hsp90 and Hsp70. This effect
can be seen 6 and even 24 h post dosing. It was hypothesized that
this prolonged exposure could translate to an extended pharmaco-
dynamic effect and ultimately to an improved dosing schedule in
the clinic. Another characteristic response to effective Hsp90 inhi-
bition is the down-regulation of HER2 a well-known substrate for
this chaperone. Similarly, phosphorylated Akt is also down-regu-
lated at the same time points.
Figure 4. X-ray crystal structure of macrocycle 40 bound to the N-terminal Hsp90
binding site.
Tissue and blood levels of 38 were also measured in this bio-
marker study. As can be seen in Table 3, rapid clearance of the
compound was observed from the blood while the tumor levels re-
mained high throughout the 24 h experiment consistent with the
biomarker results.
In conclusion, we were able to optimize potent macrocyclic
amine 8 with its hERG liability to an equipotent lactam devoid of
ion channel activity while retaining excellent physical properties.
The clear biomarker activity of lactam 38 even at 24 h post PO dos-
ing and its high exposure levels in the tumor provides relevant SAR
insight. Improved macrocyclic analogs with in vivo efficacy will be
reported in due course.
valuable SAR information. Its increased potency compared to ana-
logs 41 and 42 was expected to contribute to an improved crystal-
lization behavior. As can be seen in Figure 4, the carbonyl of the
tetrahydroindolone engages in a hydrogen bond with Tyr139 while
the benzamide interacts with Asp93 in a direct and a water-med-
iated hydrogen bond. The X-ray structure of 40 indicates that the
methyl amide is pointed toward the protein in essence explaining
the drop in activity for derivatives 41 and 42 with their bulkier
substituents.
These macrocyclic o-aminobenzamides bind to the N-terminal
ATP binding pocket of ATP (Fig. 4) and are as such competitive
Table 2
Effect of 38 on proliferation in various cell lines
Cell line
IC50 [nM]
Cell line
IC50 [nM]
A375
23
HCT116
56
WM266-4
92
T98G
42
A549
23
U87MG
80
NCI-1975
BT474
23
KB8.5
49
MDAMB361
111
KBV1
DU145
45
47
KB
22
>1000

3416
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3411–3416
J.; Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.;
References and notes
Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.; Workman, P.; Wright, L. J.
Med Chem. 2008, 51, 196.
17. Biamonte, M. A.; Van de Water, R.; Arndt, J. W.; Scannevin, R. H.; Perret, D.; Lee,
W. C. J. Med. Chem. 2010, 53, 3.
18. Barta, T. E.; Veal, J. M.; Rice, J. W.; Partridge, J. M.; Fadden, R. P.; Ma, W.; Jenks,
M.; Geng, L.; Hanson, G. J.; Huang, K. H.; Barabasz, A. F.; Foley, B. E.; Otto, J.;
Hall, S. E. Bioorg. Med. Chem. Lett. 2008, 18, 3517.
19. Huang, K. H.; Veal, J. M.; Fadden, R. P.; Rice, J. W.; Eaves, J.; Strachan, J. P.;
Barabasz, A. F.; Foley, B. E.; Barta, T. E.; Ma, W.; Silinski, M. A.; Hu, M.; Partridge,
J. M.; Scott, A.; DuBois, L. G.; Freed, T.; Steed, P. M.; Ommen, A. J.; Smith, E. D.;
Hughes, P. F.; Woodward, A. R.; Hanson, G. J.; McCall, W. S.; Markworth, C. J.;
Hinkley, L.; Jenks, M.; Geng, L.; Lewis, M.; Otto, J.; Pronk, B.; Verleysen, K.; Hall,
S. E. J. Med. Chem. 2009, 52, 4288.
20. Zapf, C. W.; Bloom, J. D.; McBean, J. L.; Dushin, R. G.; Nittoli, T.; Ingalls, C.;
Southerland, A.; Sonye, J. P.; Eid, C. N.; Golas, J. M.; Liu, H.; Boschelli, F.; Vogan,
E. M.; Hu, Y.; Levin, J. I. Bioorg. Med. Chem. Lett. 2011, 21, 2278.
21. IC50s were obtained from a standard Ionworks HT patch clamp assay.
22. Gopalsamy, A.; Shi, M.; Golas, J.; Vogan, E.; Jacob, J.; Johnson, M.; Lee, F.;
Nilakantan, R.; Petersen, R.; Svenson, K.; Chopra, R.; Tam, M. S.; Wen, Y.;
Ellingboe, J.; Arndt, K.; Boschelli, F. J. Med. Chem. 2008, 51, 373.
23. Boschelli, F.; Golas, J. M.; Petersen, R.; Lau, V.; Chen, L.; Tkach, D.; Zhao, Q.;
Fruhling, D. S.; Liu, H.; Nam, C.; Arndt, K. T. Cell Stress Chaperones 2010, 15, 913.
24. The structure has been assigned PDB ID code 3R91.
1. Borst, P.; Jonkers, J.; Rottenberg, S. Cell Cycle 2007, 6, 2782.
2. Nobili, S.; Landini, I.; Giglioni, B.; Mini, E. Curr. Drug Targets 2006, 7, 861.
3. Blagg, B. S.; Kerr, T. D. Med. Res. Rev. 2006, 26, 310.
4. Neckers, L. J. Biosci. 2007, 32, 517.
5. Isaacs, J. S.; Xu, W.; Neckers, L. Cancer Cell 2003, 3, 213.
6. Solit, D. B.; Chiosis, G. Drug Discov. Today 2008, 13, 38.
7. Whitesell, L.; Lindquist, S. L. Nat. Rev. Cancer 2005, 5, 761.
8. Maloney, A.; Workman, P. Expert Opin. Biol. Ther. 2002, 2, 3.
9. Taldone, T.; Sun, W.; Chiosis, G. Bioorg. Med. Chem. 2009, 17, 2225.
10. Messaoudi, S.; Peyrat, J. F.; Brion, J. D.; Alami, M. Anticancer Agents Med. Chem.
2008, 8, 761.
11. Drysdale, M. J.; Brough, P. A. Curr. Top. Med. Chem. 2008, 8, 859.
12. Hwang, M.; Moretti, L.; Lu, B. Curr. Med. Chem. 2009, 16, 3081.
13. Whitesell, L.; Mimnaugh, E. G.; De Costa, B.; Myers, C. E.; Neckers, L. M. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 8324.
14. Supko, J. G.; Hickman, R. L.; Grever, M. R.; Malspeis, L. Cancer Chemother.
Pharmacol. 1995, 36, 305.
15. Tian, Z. Q.; Liu, Y.; Zhang, D.; Wang, Z.; Dong, S. D.; Carreras, C. W.; Zhou, Y.;
Rastelli, G.; Santi, D. V.; Myles, D. C. Bioorg. Med. Chem. 2004, 12, 5317.
16. Brough, P. A.; Aherne, W.; Barril, X.; Borgognoni, J.; Boxall, K.; Cansfield, J. E.;
Cheung, K. M.; Collins, I.; Davies, N. G.; Drysdale, M. J.; Dymock, B.; Eccles, S. A.;
Finch, H.; Fink, A.; Hayes, A.; Howes, R.; Hubbard, R. E.; James, K.; Jordan, A. M.;
Lockie, A.; Martins, V.; Massey, A.; Matthews, T. P.; McDonald, E.; Northfield, C.