Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model

Article abstract of DOI:10.1016/j.bmcl.2011.04.102

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.

Full text of DOI:10.1016/j.bmcl.2011.04.102

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3627–3631
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor
with heterocyclic tether that shows extended biomarker
activity and in vivo efficacy in a mouse xenograft model
Christoph W. Zapf a, , Jonathan D. Bloom a, Jamie L. McBean a, Russell G. Dushin a,
⇑
Jennifer M. Golas b, Hao Liu b, Judy Lucas b, Frank Boschelli b, Erik Vogan c, Jeremy I. Levin a
a Medicinal Chemistry, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States
b Oncology Research, Pfizer, 401 N. Middletown Road, Pearl River, NY 10965, United States
c 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, heterocycle-containing tethers were explored with the intent to further improve potency and
minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently sup-
pressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activ-
ity at least 24 h post-administration consistent with elevated and prolonged exposure in the tumor.
When studied in a xenograft model, the compound demonstrated significant suppression of tumor
growth.
Received 30 March 2011
Revised 18 April 2011
Accepted 21 April 2011
Available online 28 April 2011
Keywords:
Hsp90 inhibitors
Chaperone inhibitors
Ortho-aminobenzamides
N-terminal ATP-binding site
Macrocycles
Ó 2011 Elsevier Ltd. All rights reserved.
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. Tar-
geting chaperone proteins offers a promising solution to this tradi-
tional chemotherapy dilemma, since it allows the simultaneous
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.5–10 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.11 Inhi-
bition of Hsp90 leads to the destabilization, and ultimately degra-
dation of the clients, which results in the inhibition of cell growth
and apoptosis.12
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.17 Clinical studies established this com-
pound’s unacceptable toxicology profile, preventing it from further
development.18 Optimization studies led to the discovery of
17-AAG 2 and 17-DMAG 319 which are currently in clinical trials,
but which are characterized by poor solubility and a narrow ther-
apeutic window, respectively.
Vernalis recently disclosed resorcinol 420 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.21
Serenex recently disclosed their own efforts to discover potent
small-molecule Hsp90 inhibitors that would be devoid of the
drawbacks associated with Geldanamycin and its analogs.22 Their
studies culminated in a series of 2-aminobenzamides which exhib-
ited low-nanomolar potencies in a proliferation assay. Among the
reported compounds, glycine pro-drug SNX-5422 (5) was ad-
vanced to clinical trials.23
Using structure-based drug design, a series of potent benzisox-
azoles as Hsp90 inhibitors was recently discovered.24 Continuing
the search for potent small molecule inhibitors of Hsp90, and
guided by X-ray crystallography using a structural analog of 5,
Different ATP-competitive chemotypes have evolved as potent
N-terminal Hsp90 inhibitors, several of which have transitioned
into clinical trials.13–15 While many of these clinical trials focus
on Hsp90 inhibitors as single agents for cancer therapy, combina-
tion studies with established chemotherapeutics have been de-
signed and were reported recently as well.16
⇑
Corresponding author. Tel.: +1 617 665 5602; fax: +1 617 665 5682.
E-mail address: christoph.zapf@pfizer.com (C.W. Zapf).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.04.102

3628
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3627–3631
O
O
H
2N
O
R
O
H
N
O
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
3 17-DMAG: R = NHCH2CH2NMe2
4 NVP-AUY922
5 SNX-5422
H
H
2N
O
2N
O
H
H
N
Me
NH
Me
NH
N
O
N
N
O
O
6
7
Figure 1. Structure of Geldanamycin 1, clinically relevant ansamycins 17-AAG 2, 17-DMAG 3, Vernalis’ clinical candidate NVP-AUY922 4, Serenex’ clinical candidate SNX-
5422 5 as well as previously reported macrocyclic amine 6 and lactam 7.
we were inspired to design structurally unique macrocycles25,26
derived from o-aminobenzamides (such as amine 6). These com-
pounds were shown to be potent inhibitors of Hsp90 in an enzyme
and cell-proliferation assay (HCT116) while retaining excellent sol-
ubility and microsomal stability.27 Even more recently, we dis-
closed a series of macrocyclic amides (such as lactam 7), which
demonstrated excellent tumor exposure and biomarker activity
even at 24 h post dosing while being devoid of activity at the hERG
ionchannel.28 We continued to seek compounds in this structure
class that would demonstrate efficacy in a xenograft model and
wish to disclose a design that involved the incorporation of small
amine-based heterocyclic structures into the macrocyclic tether.
This effort culminated in the discovery of macrocycle 10, which
showed in vivo efficacy in a glioma xenograft model.
As illustrated in Scheme 1, aldehyde 827 was converted to amines
9 by reductive amination with either readily available or easily
accessible optically pure building blocks, followed by removal of
the Boc-protecting group. Cyclization using Buchwald–Hartwig
conditions preceded hydrolysis of the aryl nitrile to the carboxam-
ides 10–21.
Analogs 22–27 (Fig. 2), with the exception of lactam 24, were
prepared using the same methodology as depicted in Scheme 1.
Lactam 24 was prepared from the corresponding carboxylic acid
utilizing identical chemistry as previously reported.28
H2N
O
CN
N
X
CN
N
NH2
BocHN
H
N
Br
3
n
Br
N
X
X
H
c,d
a,b
2
n
n
N
N
N
CHO
O
O
O
8
9
10 - 21
#
pos. chirality
X
n
#
pos. chirality
X
n
10
2
2
R
S
CH2
CH2
1
1
16
17
18
19
20
21
3
3
2
2
2
2
R
S
R
R
R
R
CH2
CH2
(R)-CHOH
(S)-CHF
(S)-CHNHAc
1
1
1
1
1
1
11
12
13
14
15
2
2
2
2
R
S
S
CH2
O
NH
2
2
2
2
S
NAc
(S)-CH-N(CH2)4
Scheme 1. Reagents: (a) NaBH(OAc)3, Boc-protected amine, DCE; (b) 10% TFA, DCM; (c) Pd2dba3, BINAP, NaOtBu, dioxane, toluene, 110 °C; (d) 90% H2SO4, 60 °C or 5 M NaOH,
30% H2O2, DMSO, EtOH.

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3627–3631
3629
H
H2N
O
2N
O
H2N
O
H
N
H
N
H
N
N
N
N
N
N
N
O
O
O
H2N
O
22
O
23
O
24
O
H
2N
H
2N
H
H
H
N
N
N
N
N
N
N
N
N
O
O
O
25
26
27
Figure 2. Analogs of macrocycle 10, prepared in the attempt to improve stability and hERG activity.
One of the first macrocycles prepared in this series was pyrrol-
idine derivative 10. It was designed as an analog to macrocycle 6
with the intent to improve its potency by incorporating a rigidify-
ing structural element. Several heterocycle-containing 1,2-ethy-
lenediamine derivatives are commercially available and were
thus attractive building blocks for incorporation into the linker
design. As expected, analog 10 showed an increase in potency com-
pared to amine 6, whereas its enantiomer 11 showed a substantial
reduction in binding activity (Table 1). This finding underscores the
critical nature of the stereochemical properties of the macrocyclic
tether. Ring-size is another critical parameter that has a profound
effect on potency. Compared to 10, analogs 22 and 23 differ only by
Table 1
Biological activities, profiling data, and selected calculated properties for Geldanamycin and macrocycles 10–27
#
Hsp90a
vSrcb
HCT116c
U87c
2C9d
2D6d
3A4d
Sol.e
Humanf
Mousef
Ratf
MWg
TPSAh
c log Pi
hERGj
LEk
LipEl
1m
6
7
0.040
0.110
0.082
0.096
1.037
0.126
0.096
3.324
0.106
0.201
>5
0.153
0.061
0.634
0.496
0.883
0.301
0.188
0.170
0.982
0.078
0.050
0.116
0.079
0.040
0.897
0.044
0.037
2.072
0.055
0.090
3.607
0.117
0.036
1.491
1.836
0.398
0.193
0.126
0.060
0.582
0.081
0.030
0.093
0.056
0.032
1.141
0.032
0.034
1.852
0.140
0.100
2.973
0.192
0.060
2.564
2.428
0.460
0.232
0.310
0.067
0.671
0.039
0.089
0.366
0.080
0.087
NT
0.029
0.030
NT
NT
0.421
NT
0.679
0.095
3.628
>5
NT
25
23
6
NT
0
39
À12
15
2
NT
9
46
NT
À3
0
0
NT
4
NT
0
NT
63
6
73
NT
77
71
1
34
53
NT
64
77
NT
34
32
67
NT
55
70
76
NT
NT
10
4
12
NT
8
NT
NT
>30
16
NT
27
7
>30
5
>30
NT
7
NT
>30
>30
6
NT
3
3
>30
3
21
NT
10
2
NT
5
561
409
423
435
435
449
451
450
492
435
435
451
453
492
504
421
449
449
463
421
435
163
89
106
80
80
80
90
92
101
80
80
101
80
109
84
80
80
97
80
80
80
2.1
4.1
3.5
4.3
4.3
4.8
3.7
3.7
3.3
4.1
4.1
3.1
4.3
3.0
4.4
3.9
4.8
3.2
5.4
3.7
4.3
NT
NT
NT
2.6
NT
0.9
12.5
NT
24.4
0.44
NT
NT
16.4
NT
NT
NT
NT
NT
1.5
NT
3.4
0.26
0.32
0.32
0.31
0.26
0.29
0.30
0.23
0.27
0.29
NT
0.29
0.31
0.24
0.24
0.27
0.28
0.29
0.28
0.27
0.31
5.3
2.9
3.6
2.7
1.7
2.1
3.3
1.8
3.7
2.6
NT
3.7
2.9
3.2
1.9
2.2
1.7
3.6
1.4
2.3
2.8
>100
>100
2324
66
52
29
>100
>100
>100
NT
67
3
NT
71
6
>100
NT
35
49
16
À5
34
NT
16
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
3
À3
>30
14
23
NT
3
4
0
NT
33
9
NT
69
6
4
5
NT
NT
NT
5
NT
3
NT
NT
NT
11
NT
6
NT
6
8
NT
7
5
1.559
1.083
0.564
NT
2
NT
À4
23
12
25
74
NT
2
NT
3
0.067
8
For experimental details regarding assay conditions see Ref. 24.
a
Enzyme IC50
(
l
M).
Cell-based functional assay IC50
Cell-proliferation EC50 M).
M.
b
c
(lM).
(
l
l
d
e
f
% Cyp-inhibition at 3
Solubility ( g/mL).
l
t1/2 in microsomes (min).
Molecular weight.
Total polar surface area.
Calculated partition ratio.
Ion channel IC50 (lM).
Ligand efficiency.
Lipophilic efficiency.
In-house data.
g
h
i
j
k
l
m

3630
C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3627–3631
the pyrrolidine ring, with the goal of enhancing the properties
associated with 10. A high c log P was presumably predictive of
its low stability in microsomes of the three indicated species
(Table 1). Incorporation of a hydroxyl group (18) led to a reduction
in lipophilicity but did not improve stability. Addition of a fluorine
substituent (19) lowered the pKa of the compound, which led to an
improvement of the compound’s potency at the hERG ion channel
without affecting potency. However, no improvement of micro-
somal stability was observed, possibly due to the unchanged
c log P. Addition of an acetamide (20) or pyrrolidine substituent
(21) led to analogs with substantially reduced activity in the en-
zyme and cell-assays.
An X-ray crystal structure for macrocycle 10 bound to the
N-terminal ATP-binding site of Hsp90 was obtained.30 As can be
seen in Figure 3, the carbonyl of the tetrahydroindolone engages
in a hydrogen bond with Tyr139, while the benzamide interacts
with Asp93 in a direct and a water-mediated hydrogen bond. The
nitrogen of the tether forms an additional water-mediated interac-
tion with the main chain carbonyl of Asn51. Figure 3 shows a sec-
ond water molecule proximal to the benzamide interacting with
Leu48 and Ser52, representing the dense network of conserved
water molecules characteristic for the N-terminal ATP-binding site
of Hsp90.
Figure 3. Macrocycle 10 bound to the N-terminal ATP-binding site of Hsp90.
Hydrogen bonds (black dotted lines) are labeled with distances in Å. A portion of the
peptide has been omitted for clarity.
Figure 3 also highlights the proximity of Lys58 to the heterocy-
clic portion of the tether. This provides a structural explanation for
the lack of potency of analogs bearing basic functionality
approaching this side-chain.
The o-aminobenzamide-derived macrocyclic compounds bind
to the N-terminal ATP binding pocket of ATP (Fig. 3) and are as such
competitive 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.
When 10 was submitted to the Invitrogen panel of 59 kinases, it
was found that this compound displays only modest inhibitory
one carbon atom, but exhibit a substantial reduction in activity.
Likewise, removal of the basicity of the tether by conversion to
an amide (24)—a strategy that had been productive previ-
ously28—leads to a significant loss in potency in this case.
Parallel to these efforts, the ring size and nature of the hetero-
cyclic moiety within the tether was varied as well. Thus, stereo-
chemically defined analogs 12–14 were prepared with
a
piperidine, morpholine and piperazine, in the linker, respectively
(priority rules lead to a formal switch in stereochemical designa-
tion, Scheme 1). While 12 and 13 showed essentially identical
activity compared to 10, the drop in activity for 14 can be ex-
plained by the proximity of Lys58 (Fig. 3). Indeed, X-ray analysis
of 14 reveals a water mediated interaction of the distal piperazine
nitrogen with Lys58 (structure not shown). As expected, installa-
tion of the acetamide in analog 15 restores enzyme potency, pro-
viding a clear SAR trend for this series.
We had previously demonstrated that the potency of these
macrocycles depends significantly on the overall conformational
flexibility in the tether.27,28 Extension of this concept to macrocycle
12 led to the design of analog 25 (Fig. 2), which was derived from
an aminomethyl piperidine building block,29 incorporating the
stereochemically defined additional methyl group. Based on
molecular modeling, analog 25 was the only diastereomer consid-
ered for this effort that did not yield the anticipated increase in
activity. Based on this result, it was concluded that the heterocyclic
tether itself appears to provide maximum productive rigidity com-
pared to the acyclic tethers as in 6.
activity for FYN (IC50 = 22
ated tyrosine kinase, and inhibits the other kinases with an
IC50 >50 M.
lM), a SRC-related membrane-associ-
l
Compound 10 was evaluated in a biomarker study in a xeno-
graft model using U87 tumors (Fig. 4). When administered at
100 mg/kg iv, the compound clearly elicits a heat-shock response,
characterized by an up-regulation of Hsp70, which is detectable
even 24 h post dosing. Another characteristic response to effective
Hsp90 inhibition, which was detected in the biomarker study, is
Control
24 h
HSP 90
HSP 72
pAKT
pS6
An unexpected result was obtained when the connectivity of
the pyrrolidine moiety in 10 was altered by moving the methylene
group from position 2 to 3, de facto increasing the ring-size from
12 to 13. While again a clear stereochemical preference was ob-
served for the two analogs 16 and 17, the former was quite potent
when considering that other 13-membered macrocycles had been
substantially less active. By removing the methylene unit adjacent
to the aniline nitrogen in 10 or 12 while maintaining connectivity
to the 3-position of the heterocycle, 12-membered macrocycles 26
and 27 were obtained. In this instance, piperidine 27 was superior
to pyrrolidine analog 26 and showed comparable potency to pyr-
rolidine 10, without improving microsomal stability.
Actin
Figure 4. Biomarker results for compound 10 when dosed at 100 mg/kg iv in U87
bearing nude mice.
Table 2
Exposure levels of 10 in U87 xenograft tumors
Dose (mg/kg)
Route
Plasma (ng/mL) 24 h
Tumor (ng/g) 24 h
25
50
75
100
100
PO
PO
PO
PO
iv
18
34
67
103
90
109
303
476
198
1463
This latter group of analogs led to the conclusion that this con-
nectivity pattern did not provide any of the required improve-
ments. Thus, attention was directed toward the substitution of

C. W. Zapf et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3627–3631
3631
1600
1400
1200
1000
800
24 h after dosing and its pharmacokinetic parameters (Table 3)
showed a good half-life (t1/2) and exposure (AUC0–inf), low plasma
clearance (Clp), high volume of distribution at steady-state (Vss)
and high bioavailability (%F).
control
100 mpk iv day 0
100 mpk iv day 0 & 4
References and notes
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 Discovery Today 2008, 13, 38.
7. Johnson, V. A.; Singh, E. K.; Nazarova, L. A.; Alexander, L. D.; McAlpine, S. R. Curr.
Top. Med. Chem. 2010, 10, 1380.
600
8. Li, Y.; Zhang, T.; Schwartz, S. J.; Sun, D. Drug Resist. Updates 2009, 12, 17.
9. Janin, Y. L. Drug Discovery Today 2010, 15, 342.
400
10. Winssinger, N.; Fontaine, J. G.; Barluenga, S. Curr. Top. Med. Chem. 2009, 9, 1419.
11. Whitesell, L.; Lindquist, S. L. Nat. Rev. Cancer 2005, 5, 761.
12. Maloney, A.; Workman, P. Expert Opin. Biol. Ther. 2002, 2, 3.
13. Drysdale, M. J.; Brough, P. A. Curr. Top. Med. Chem. 2008, 8, 859.
14. Messaoudi, S.; Peyrat, J. F.; Brion, J. D.; Alami, M. Anticancer Agents Med. Chem.
2008, 8, 761.
200
-2
0
2
4
6
8
10
days
15. Taldone, T.; Sun, W.; Chiosis, G. Bioorg. Med. Chem. 2009, 17, 2225.
16. Hwang, M.; Moretti, L.; Lu, B. Curr. Med. Chem. 2009, 16, 3081.
17. Whitesell, L.; Mimnaugh, E. G.; De Costa, B.; Myers, C. E.; Neckers, L. M. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 8324.
Figure 5. In vivo efficacy of analog 10 in U87 glioma bearing nude mice.
18. Supko, J. G.; Hickman, R. L.; Grever, M. R.; Malspeis, L. Cancer Chemother.
Pharmacol. 1995, 36, 305.
Table 3
19. 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.
20. 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.
J.; Pearl, L. H.; Prodromou, C.; Ray, S.; Raynaud, F. I.; Roughley, S. D.; Sharp, S. Y.;
Surgenor, A.; Walmsley, D. L.; Webb, P.; Wood, M.; Workman, P.; Wright, L. J.
Med. Chem. 2008, 51, 196.
PK parameters for 10 in male CD-1 mice following a single 2 mg/kg IV or 10 mg/kg
oral dose
t1/2 (h)
AUC0–inf (h ng/mL)
Clp (mL/min/kg)
19
Vss (l/kg)
%F
iv
PO
4.6
5.2
1738
6455
5.3
74%
21. Biamonte, M. A.; Van de Water, R.; Arndt, J. W.; Scannevin, R. H.; Perret, D.; Lee,
W. C. J. Med. Chem. 2010, 53, 3.
22. 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.
the down-regulation of pS6 and pAKT, two known substrates for
this chaperone.
Tissue and blood levels of 10 were also measured following iv
and oral dosing. As can be seen in Table 2, clearance of the com-
pound was observed from the blood 24 h post dosing. Compound
levels in the tumor remained elevated throughout the 24 h exper-
iment, generally in a dose-dependent manner consistent with the
biomarker results. However, tumor exposure was substantially
higher after iv compared to oral dosing.
Finally, compound 10 was characterized in a xenograft model
using U87 bearing nude mice (Fig. 5). Compared to the control
group, the macrocycle significantly suppressed tumor growth
when dosed iv once at 100 mg/kg on day 0. The compound was
even more effective when dosed twice per week at 100 mg/kg on
days 0 and 4.
23. 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.
24. 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.
25. Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. Nat. Rev. Drug Discov. 2008, 7,
608.
26. Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961.
27. 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.
28. Zapf, C. W.; Bloom, J. D.; McBean, J. L.; Dushin, R. G.; Nittoli, T.; Otteng, M.;
Ingalls, C.; Golas, J. M.; Liu, H.; Lucas, J.; Boschelli, F.; Vogan, E. M.; Hu, Y.; Levin,
J. I. Bioorg. Med. Chem. Lett. 2011, in press, doi:10.1016/j.bmcl.2011.03.112.
29. Froelich, O.; Desos, P.; Bonin, M.; Quirion, J.-C.; Husson, H.-P.; Zhu, J. J. Org.
Chem. 1996, 61, 6700.
In conclusion, compound 10 was demonstrated to be a potent
Hsp90 inhibitor in enzyme and cell-based assays. It showed excel-
lent biomarker activity and a significant effect on tumor growth
suppression. Furthermore, it demonstrated good tumor exposure
30. The structure has been assigned PDB ID code 3R92.