Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres

Article abstract of DOI:10.1016/j.bmcl.2010.02.021

A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compound

Full text of DOI:10.1016/j.bmcl.2010.02.021

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2229–2233
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres
a,
a
b
a
Frederick Cohen a, , Michael F. T. Koehler , Philippe Bergeron , Linda O. Elliott , John A. Flygare ,
Matthew C. Franklin c, Lewis Gazzard a, Stephen F. Keteltas a, Kevin Lau a, Cuong Q. Ly a, Vickie Tsui a,
Wayne J. Fairbrother c
*
*
a Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA
b Department of Biochemical Pharmacology, 1 DNA Way, South San Francisco, CA 94080, USA
c Department of Protein Engineering Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthe-
sized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence
polarization assay. The most potent of these compounds, 19a and 33b, were found to have Ki’s of 20–
30 nM against ML-IAP and 50–60 nM against XIAP-BIR3.
Received 7 January 2010
Revised 3 February 2010
Accepted 3 February 2010
Available online 8 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
IAP antagonist
Peptidomimetic
Protein–protein interaction
Programmed cell death, or apoptosis, is a crucial process in
development for maintaining homeostasis and for the removal of
damaged or malignant cells. This pathway is tightly controlled by
a number of positive and negative regulatory elements. The inhib-
itor of apoptosis (IAPs) proteins negatively regulate this process
through a variety of mechanisms including direct inhibition of
effector caspase enzymes and modulation of TNF receptor-medi-
ated signaling pathways.1 Members of the IAP protein family are
upregulated in various cancers and promote resistance to chemo-
therapy. Thus inhibition of these proteins may be a new therapeu-
tic mechanism for treating cancer.2
Following the discovery that short peptides could disrupt the
interaction of the IAPs with the amino terminus of caspases,3,4 there
have been multiple efforts to develop molecules with reduced pep-
tide character that possess the appropriate potency, permeability
and pharmacokinetic properties to be a useful therapeutic agent.5–7
In our effort to develop such a molecule, we began with the modified
peptide Ala-Val-Pro-2,2-diphenethylamine (1).8 This lead binds to
the third XIAP baculoviral inhibitor of apoptosis repeat (BIR3)
domain with a Ki of 345 nM and to the MLXBIR3SG (a chimeric BIR
domain that preserves the native ML-IAP peptide-binding site9) with
a Ki of 43 nM.6 The 2.3 Å resolution crystal structure (PDB 3F7G) of 1
bound to the ML-IAP BIR domain (Fig. 1A) revealed that the NH and
carbonyl of the P2 valine make specific contacts with the backbone
of the BIR domain (Fig. 1B).
* Corresponding authors. Tel.: +1 650 225 1000; fax: +1 650 467 8922.
E-mail addresses: fcohen@gene.com (F. Cohen), koehler.michael@gene.com
(M.F.T. Koehler).
Figure 1. (A) Crystal structure of peptide 1 in complex with MLXBIR3SG at 2.3 Å
resolution. The key P1 and P4 binding pockets are labeled (PDB 3F7G). (B)
Illustration of key electrostatic and hydrogen bonds.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.021

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F. Cohen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2229–2233
Table 1
4
Br
Structure and affinity for thiazole antagonistsa
Ar
O
BocN
5 R = Boc
6 R = H
N
R
O
R
N
O
c
NH2
Ar
HN
N
S
N
H
X
b
N
O
S
Ar
2 X = O
3 X = S
A
B
C
a
d or e,f,g
Compd
Ar
Ph
R
Kib (mM)
XIAP-BIR3
0.19
MLXBIR3SG
X
O
R
N
11a
B
1.2
BocN
N
O
H
O
BocN
N
N
H
CO2H
S
9 R = tBu
10 R = Cy
X
Ar
11b
11c
11d
11e
11f
X = CH
A
B
C
B
C
B
0.068
0.068
0.035
0.019
0.140
0.075
0.22
0.11
0.10
0.068
0.040
0.045
7 X = CH2
8 X = O
h
11
see Table 1
X = CF
X = N
Scheme 1. Synthesis of thiazole amide isosteres. Reagents and conditions: (a)
Lawesson’s reagent, toluene, 50 °C, 1 h (90%); (b) 0.95 equiv pyridine, MeCN, 50 °C;
(c) TFA, CH2Cl2; (d) 7 or 8, DIC, HOAt, CH2Cl2; (e) Boc-t-Leu-OH, HATU, DIPEA, DMF;
(f) TFA, CH2Cl2; (g) Boc-N-Me-Ala-OH, EDC, HOBT; (h) TFA, HPLC.
11g
11h
11i
A
B
0.13
0.10
0.18
0.20
O
By contrast, the P3–P4 amide bond does not make any specific
contacts with the protein, and thus was a good candidate for
replacement with a heterocycle. Several potential heterocycles
were evaluated for geometric fit, modular synthesis, and drug-like-
ness. From this analysis a thiazole appeared attractive, as did a 4-
substituted benzothiazole.10
11j
B
A
0.12
0.13
0.12
11k
0.047
The synthesis of the thiazole-containing antagonists (Scheme 1)
began with Boc-proline amide 2, which was converted to the thio-
amide 3 with Lawesson’s reagent in toluene at 50 °C. Use of higher
temperatures led to complete racemization. Condensation with
bromomethyl ketones proceeded smoothly under optimized con-
ditions with 0.95 equiv of pyridine. Use of more pyridine or a
stronger base prevented the dehydration step of the condensation
and led to isolation of the hydroxy thiazoline intermediate, while
use of less base resulted in significant removal of the Boc group
and degradation of the product. After intermediate 6 was purified
by chromatography, the Boc group could be cleanly removed. The
antagonists were rapidly completed using the convergent peptide
coupling procedure of Carpino.11 Thus dipeptides 7 or 8 could be
coupled in high yield with no evidence of epimerization of the P2
residue. Antagonists containing the tert-leucine residue at P2 were
assembled stepwise with Boc-t-Leu, then Boc-N-Me-Ala. Finally,
the Boc group was removed with trifluoroacetic acid in DCM, and
the product purified by reverse-phase HPLC. The structures of
these analogs are listed in Table 1.
Antagonists were assayed for binding to the BIR3 domain of
XIAP and MLXBIR3SG using a previously reported fluorescence
polarization assay (Table 1).6 The simple phenyl analog 11a lost
significant affinity for MLXBIR3SG relative to our design starting
point 1, while a slight increase in affinity for XIAP-BIR3 was ob-
served. Extending the P4 group to a naphthyl substituent dramat-
ically increased affinity of the corresponding analog for both BIR
domains. Further gains in affinity were found by substituting the
naphthyl group with a small electron-withdrawing group at the
4-position as in 11e–g. Affinity for the BIR domains could also be
increased by adding a 5,6-fused ring system such as benzofuran
in 11h–i or benzothiophene 11k.
a
Ki determined as described in Ref. 6.
Average of two measurements.
b
(PhSO2)2NF yielded, after separation from residual starting mate-
rial, the fluorinated derivative 13.13 While direct fluorination was
unsuccessful, direct halogenation of 12 with NCS or NBS yielded
chloro or bromo derivatives 14 or 15 in moderate yield. Bromo
derivative 15 could be further elaborated by coupling with Zn(CN)2
BocN
BocN
a, or, b,
N
S
N
or, c
S
H
R1
12
1
13
R = F
1
14
R = Cl
15 R1 = Br
d
R2
16 R1 = CN
Bu3Sn
e
1
R2
17
R
=
X
f
O
g, h
HN
HN
N
N
H
N
O
S
N
S
R1
In general, the nature of the P2 residue had little effect on affin-
ity. The cyclohexyl group provided an opportunity to modify
molecular properties. For instance, the substitution of a pyran for
the cyclohexyl lowers the cLog P of 11c from 4.9 to 2.5 for 11d.12
Chemistry was developed to investigate the effect of substitu-
ents at the 5-position of the thiazole (Scheme 2). Deprotonation
of naphthyl thiazole 12 with n-BuLi followed by treatment with
19
R1
18
Scheme 2. Synthesis of 5-subsituted thiazoles. Reagents and conditions: (a) n-BuLi
(PhSO2)2NF, THF À78 °C (18%); (b) NCS, 1:1 CH2Cl2/hexanes (50%); (c) NBS, CH2Cl2
(66%); (d) Zn(CN)2, PdCl2DPPF DMF, H2O, mWave, 130 °C 75%; (e) Bu3SnCCR2,
Pd(PPh3)4, LiCl, PhMe, D (60%); (f) TFA, DCM (quant.); (g) 7 or 8, DIC, HOAt, CH2Cls;
(h) TFA, HPLC (30–60%, two steps).

F. Cohen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2229–2233
2231
Table 2
Table 3
Structure and affinity of 5-substituted thiazolesa
Structure and affinity of benzothiazolesa
X
O
O
HN
N
HN
N
N
N
H
R
N
H
N
O
S
O
S
R1
Compd
R
Kib (mM)
Compd
X
O
CH2
O
R1
Kib (mM)
MLXBIR 3SG
XIAP-BIR3
MLXBIR3SG
XIAP-BIR3
26a
26b
26c
26d
Me
i-Pr
Bn
0.94
0.19
0.15
0.036
2.7
2.8
0.71
0.053
19a
19b
19c
F
Cl
CN
0.024
0.035
0.032
0.068
0.21
0.069
Ph
19d
19e
O
O
H
Me
0.031
0.038
0.16
0.16
26e
26f
0.05
0.06
0.20
0.46
19f
O
O
0.031
0.031
0.14
0.14
OMe
OH
19g
a
Ki determined as described in Ref. 6.
Average of two measurements.
b
26g
26h
26i
26j
26k
26l
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
0.16
0.73
0.14
0.068
0.13
0.13
0.044
0.055
0.058
0.046
0.049
0.045
or an alkynyl stannane under palladium catalysis. These elaborated
thiazoles were deprotected and coupled to dipeptides 7 or 8 as de-
scribed in Scheme 2.
a
Ki determined as described in Ref. 6.
Average of two measurements.
Analogs substituted with F and CN (19a, 19c) had higher affinity
for boththeXIAP-BIR3and MLXBIR3SGdomains (Table2). Thelarger
chloro and alkyne substituents retained affinity for XIAP-BIR3, but
lost affinity for MLXBIR3SG. These were small, but reproducible,
variations for which the structural basis was not clear (vide infra).
Having succeeded in replacing the P3–P4 amide bond with a
thiazole, we were encouraged to also try a benzothiazole. These
were synthesized as shown in Scheme 3. Boc-proline was coupled
to 2-substituted anilines using standard peptide coupling condi-
tions. Subsequent Suzuki–Miyaura coupling gave access to a vari-
ety of 2-aryl substituted analogs to probe the P4 pocket.
Conversion to the thioamide using Lawesson’s reagent at 80 °C
gave moderate yields and resulted in some racemization of the
proline. These thioamides were oxidatively cyclized to the benzo-
thiazole using basic potassium ferricyanide.14 The antagonists
were completed using the previously described fragment coupling
and deprotection sequence. Purification by reverse-phase HPLC re-
b
moved the minor diastereomer generated during formation of the
thioamide and gave rise to analogs 26a–l, for which binding affin-
ities for both XIAP-BIR3 and MLXBIR3SG are shown in Table 3.
From our initial set of analogs we determined that an unsubsti-
tuted phenyl ring in the 4-position of the benzothiazole (26d), gave
the highest affinity for both BIR domains. Replacement with an iso-
propyl (26b) or benzyl (26c) group reduced the affinity 4–5-fold,
and a simple methyl group in the P4 pocket resulted in a 26-fold
reduction in affinity (26a). Substituting the phenyl ring in the P4
pocket revealed more subtle variations in the SAR. The 3-pyridyl
compound 26e was only slightly less potent than 26d, and the 4-
pyridyl compound 26f was equipotent in binding the BIR3 domain
of XIAP, but bound to MLXBIR3SG with eightfold less affinity.
We continued to assess the binding preferences of the P4 pocket
by substituting the phenyl ring exhaustively with fluorine and
chlorine (26g–l). Most of these compounds showed very small dif-
ferences in affinity from one another and from the unsubstituted
26a. The exception was the 2-chloro substituted compound 26g,
which bound both BIR domains with significantly lower affinity.
This was attributed either to an unfavorable contact between the
chlorine atom and the protein or, more likely, to an increase in
the torsion angle between the benzothiazole and the 2-chloro-
phenyl rings which, in turn, produces a less favorable interaction
with the P4 pocket.
H2N
R
21
BocN
22 R = alkyl
23
R
BocN
HO2C
R = I
NH
O
c
O
a R = Me, Ph, i-Pr, Bn
b R = I
24 R = Ar
20
We turned our attention to modifications of the benzothiazole
itself in an effort to modify the properties of our molecules. As a
consequence of the peptidic portion of our molecules, the topolog-
ical polar surface area (tPSA) of 26a was 73.8 Å2, however the
cLog P was 5.1, which decreases the probability of successful devel-
opment.15 We experimented with the placement of nitrogen atoms
in the phenyl ring of the benzotrizole, addition of which increases
the tPSA by approximately 13, while reducing the cLog P by nearly
a full unit.
BocN
f
d,e
HN
N
S
N
N
H
O
N
R
S
26
R
25
Scheme 3. Reagents and conditions: (a) HATU, DIPEA, DMF, 50 °C; (b) cyanuric
fluoride, pyridine, CH2Cl2; (c) ArB(OH)2, Pd(PPh3)4, K2CO3, DMF, H2O; (d) Lawesson’s
reagent, toluene, 80 °C; (e) K3Fe(CN)6, NaOH, H2O, 85 °C; (f) TFA, toluene, CH2Cl2;
(g) 7, DIC, HOAt, CH2Cl2; (h) TFA, toluene, CH2Cl2, HPLC.
We began our synthesis of the aza-benzothiazoles by preparing
the biphenyl amides 31a–d (Scheme 4). Inclusion of a chloro sub-
stituent ortho to the aniline nitrogen provided the desired aza-ben-

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F. Cohen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2229–2233
Table 4
I
Affinity of aza-benzothiazolesa
BocHN
Cl
a, b
Compound
Kib (mM)
CbzN
N
XIAP-BIR3
MLXBIR3SG
d or
c
NH Ph
27
33a
33b
33c
33d
33e
0.041
0.073
0.26
0.051
0.037
0.036
0.049
0.13
0.032
0.024
O
Cl
e, f
Cl
Z
a
H2N
Cl
X
Y
Z
Y
X
a
31a X = N; Y = Z = CH
31b X = Z = CH; Y = N
31c X = Z = N; Y = CH
31d X = Z = N; Y = CCH3
Ki determined as described in Ref. 6.
b
28 X = Z = CH; Y = N
29 X = Z = N; Y = CH
Average of two measurements.
30 X = Z = N; Y = CCH3
BIR3SG and compounds 11b (PDB 3GT9) and 26d (PDB 3GTA) were
determined to resolutions of 1.7 Å (Fig. 2). Key contacts observed in
the structure of 1 in complex with the ML-IAP BIR domain (Fig. 1A)
are conserved in the complexes with 11b and 26d. In particular,
hydrogen bonds with the main chain of Gln132 and the side chain
carboxylate of Asp138 are maintained. The hydrophobic contacts
in the P4 pocket differ in our new complexes. In the case of 11b,
the 1-naphthyl group makes extensive hydrophobic contacts with
the side chain of Lys121. In compound 26d, the 4-phenyl ring
makes similar hydrophobic contacts with the Lys side chain, while
CbzN
g, h, i
O
H
N
N
N
S
N
H
N
Ph
O
Ph
S
X
Z
Y
Z
X
33a X = N; Y = Z = CH
33b X = Z = CH; Y = N
33c X = Z = N; Y = CH
32a X = N; Y = Z = CH
32b X = Z = CH; Y = N
32c X = Z = N; Y = CH
32d X = Z = N; Y = CCH3
Y
33d X = Z = N; Y = CCH3
the six-membered ring of the benzothiazole makes a close
p–p
Scheme 4. Reagents and conditions: (a) PhB(OH)2, Pd(PPh3)4, K2CO3, DMF, H2O
(27–83%); (b) TFA, toluene, CH2Cl2, 40 °C (100%); (c) Cbz-Pro-COCl, pyridine, CH2Cl2,
40 °C (99%); (d) for 31a and 31b–c: Lawesson’s reagent, toluene, 100 °C (51–75%);
(e) for 31b: Tf2O, pyridine, CH2Cl2, 0 °C, then aq (NH4)2S (35%); (f) DMF, 120 °C
(96%); (g) TFA, thioanisole, 40 °C (100%); (h) 7, DIC, HOAt, CH2Cl2; (i) TFA, HPLC (30–
60%, two steps).
interaction with the amide of Gln132.18 In both cases, the replace-
ment for the P3–P4 amide successfully presents the aromatic side
chain appropriately to the P4 pocket, which results in the observed
high affinity binding.
Beginning from the crystal structure of peptide 1, we were suc-
cessful in replacing the P3–P4 amide bond with both a thiazole and
a benzothiazole amide isostere. A series of compounds were pro-
duced to evaluate the SAR of substitutions both on the heterocycle
as well as on the hydrophobic portion of the molecules extending
into the P4 pocket. In the thiazole series, a naphthalene or benzo-
thiophene in the 4-position was found to be optimal for high affin-
zothiazole16 upon conversion to the thioamide using either Lawes-
son’s reagent or Charette’s method of conversion to the pyridinium
triflate salt and subsequent cleavage with (NH4)2S.17 Our standard
peptide coupling and deprotection gave access to the compounds
33a–d. We completed the synthesis of 33e using a route nearly
identical to that used for making our original benzothiazoles
(Scheme 5).
We observed that these aza-benzothiazoles bound to both BIR
domains with near equal affinity (Table 4), and were essentially
equipotent to their benzothiazole analogs. The exception was dia-
za-benzothiazole 33c dropped 3–7-fold in affinity. Interestingly,
the affinity was recovered when the ring was substituted with a
methyl group (33d). The basis for this improved affinity remains
unclear, as this region appears to be solvent exposed in the bound
state (vide infra).
To gain a more detailed understanding of the interactions be-
tween the thiazole-containing IAP antagonists and the BIR domain
of ML-IAP, the crystal structures of complexes between MLX-
Ph
BocN
H2N
b, c
a
NH Ph
N
N
O
34
35
BocN
S
O
d, e, f
H
N
N
N
N
H
N
O
Ph
S
Ph
N
N
36
33e
Scheme 5. Reagents and conditions: (a) Boc-Pro-OH, EDC, DIPEA; (b) Lawesson’s
reagent, toluene, 100 °C; (c) K3Fe(CN)6, NaOH, H2O, 120 °C; (d) TFA, toluene, CH2Cl2;
(e) TFA, toluene, CH2Cl2; (f) 7, DIC, HOAt, CH2Cl2; (g) TFA, toluene, CH2Cl2, HPLC.
Figure 2. Crystal structures of 11b (PDB 3GT9) and 26d (PDB 3GTA) in complex
with MLXBIR3SG at 1.7 Å resolution.

F. Cohen et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2229–2233
2233
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ity binding to either BIR domain. Affinity could be further im-
proved through the inclusion of a small electronegative substituent
at the 4-position of the naphthalene. A similar improvement in
affinity was observed when the 5-position of the thiazole was
substituted with electronegative functional groups. When the
P3–P4 amide bond was replaced with a benzothiazole, the P4 pock-
et appears to accommodate a variety of aromatic rings with rela-
tively small differences in affinity for the BIR domain of ML-IAP
(MLXBIR3SG) and the BIR3 domain of XIAP. One notable exception
was the reduced affinity of the 2-chloro phenyl substitution, which
we believe to be the result of an alteration of the torsion angle be-
tween the benzothiazole and 2-chlorophenyl rings. Inclusion of
nitrogen into the benzothiazole ring, undertaken with an eye to
improving the physical properties of the molecules, did not signif-
icantly alter the affinity of these molecules for the BIR domains.
Crystal structures of several of the molecules complexed to the
MLXBIR3SG protein supported our hypothesis that the critical rela-
tionship for high affinity binding to this protein is the favorable
presentation of an aromatic ring or rings for binding in the P4
pocket.
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Acknowledgments
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We thank members of the Analytical and Purification groups
within Genentech Discovery Chemistry for support. X-ray crystal-
lographic data we collected in part at the Stanford Synchrotron
Radiation Light Source, a national user facility operated by Stanford
University on behalf of the US Department of Energy, Office of Ba-
sic Energy Sciences. The SSRL Structural Molecular Biology Pro-
gram is supported by the Department of Energy, Office of
Biological and Environmental Research, and by the National Insti-
tutes of Health, National Center for Research Resources, Biomedical
Technology Program, and the National Institute of General Medical
Sciences, and at The Advanced Light Source which is supported by
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