Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins

Article abstract of DOI:10.1021/jm701358v

A series of acylpyrogallols were designed, synthesized, and evaluated as small-molecule inhibitors of antiapoptotic Bcl-2 proteins. The most potent compound 9 (TM-179) binds to Bcl-2 with an IC₅₀ of 170 nM and to Mcl-1 with a K_i of 3

Full text of DOI:10.1021/jm701358v

J. Med. Chem. 2008, 51, 717–720
717
Acylpyrogallols as Inhibitors of Antiapoptotic
Bcl-2 Proteins
Guozhi Tang, Zaneta Nikolovska-Coleska, Su Qiu,
Chao-Yie Yang, Jie Guo, and Shaomeng Wang*
ComprehensiVe Cancer Center and Departments of Internal
Medicine, Pharmacology, and Medicinal Chemistry, UniVersity of
Michigan, 1500 E. Medical Center DriVe,
Ann Arbor, Michigan 48109
ReceiVed NoVember 19, 2007
Figure 1. Representative small-molecule inhibitors of Bcl-2 proteins.
Abstract: A series of acylpyrogallols were designed, synthesized, and
evaluated as small-molecule inhibitors of antiapoptotic Bcl-2 proteins.
The most potent compound 9 (TM-179) binds to Bcl-2 with an IC50 of
170 nM and to Mcl-1 with a Ki of 37 nM. Compound 9 potently inhibits
cell growth and induces apoptosis in human breast and prostate cancer
cell lines.
Apoptosis, or programmed cell death, is a cellular process
critical to normal development and homeostasis of multicellular
organisms. It is now recognized that dysfunction of the apoptosis
machinery is a hallmark of cancer.1–3 Defects in the apoptosis
machinery confer apoptosis resistance to therapeutic agents on
cancer cells and makes current anticancer therapies less effective,
leading ultimately to their failure. Targeting critical apoptosis
regulators as a means of overcoming apoptosis resistance of
cancer cells is a promising strategy in cancer therapy.
Figure 2. Design of acylpyrogallols as new inhibitors of the Bcl-2
proteins.
The Bcl-2 family proteins comprise a class of central arbiters
of apoptosis and include antiapoptotic members Bcl-2, Bcl-xL,
and Mcl-1 and proapoptotic members Bim, Bid, Bad, Bak, and
Bax.4–7 The antiapoptotic Bcl-2 proteins, including Bcl-2, Bcl-
xL, and Mcl-1, are overexpressed in many cancer cell lines and
human cancer tissues. Such overexpression protects cancer cells
from the apoptosis caused by current anticancer therapies and
plays a role in the failure of conventional anticancer drugs.4–7
These antiapoptotic Bcl-2 proteins are therefore considered to
be promising molecular targets for the design of novel anticancer
drugs.
Although the precise mechanism by which Bcl-2 proteins
regulate apoptosis in cells is still under intense investigation
and not completely understood,8 it is clear that antiapoptotic
Bcl-2 proteins effectively inhibit apoptosis, at least in part by
directly binding to proapoptotic Bcl-2 proteins such as Bim,
Bid, and Bad. Experimentally determined three-dimensional
structures of Bcl-2, Bcl-xL, and Mcl-1 show that these proteins
contain a well-defined hydrophobic surface binding groove,
known as the BH3 binding groove, into which Bid, Bim, Bad,
or Noxa binds.9–11 Small molecules designed to bind to the BH3
binding groove in these antiapoptotic Bcl-2 proteins and to block
their interactions with proapoptotic Bcl-2 members are predicted
to promote apoptosis in cancer cells and represent a promising
new cancer therapeutic strategy. Although a number of groups,
including ours, have reported the discovery and design of
nonpeptidic inhibitors of the antiapoptotic Bcl-2 proteins (Figure
1),12–22 design and development of potent and druglike small-
molecule inhibitors against these antiapoptotic Bcl-2 proteins
remain as one of the most challenging tasks in modern drug
discovery and medicinal chemistry. In this paper, we report the
design, synthesis, and evaluation of a series of acylpyrogallol
analogues as inhibitors of the antiapoptotic Bcl-2 proteins.
Previously, we have reported the discovery of (-)-gossypol
(2) as a pan inhibitor of Bcl-2, Bcl-xL, and Mcl-1, with Ki values
of 320, 480, and 180 nM, respectively.19 Using 2 as the initial
lead compound and a structure-based strategy, we also designed
several new classes of small-molecule inhibitors, including 3,
to target Bcl-2, Bcl-xL, and Mcl-1 proteins.20–22 We report
herein structure-based design, synthesis, and evaluation of
acylpyrogallols as new inhibitors of the antiapoptotic Bcl-2
proteins.
Our computational modeling studies predicted that 2 forms
a hydrogen bonding network with residues Arg146 and Asn143
in Bcl-2 through its aldehyde group and the adjacent hydroxyl
groups on one of its naphthalene rings, while the isopropyl group
on the same naphthalene ring is inserted into a hydrophobic
pocket in Bcl-2.20,21 These groups in part mimic the interactions
of Asp99, Phe101, and Asn102 in the Bim peptide with Bcl-2
protein. On the basis of the predicted binding model for 2,
pyrogallol 4 was designed to mimic the hydrogen bonding and
part of the hydrophobic interactions between 2 and Bcl-2
(Figures 2 and 3).21 Compound 4 was previously used as the
starting point for the design of 3.21
The predicted binding model showed that the carbonyl group
in 4 forms a hydrogen bond with Y108 in Bcl-2 (Figure 3). We
investigated if the tetrahydroisoquinoline amide in 4 can be
replaced by a benzoyl group, which led to the design of 5.
Modeling predicted that the binding of 5 to Bcl-2 is similar to
that of 4. While the carbonyl group in 5 forms a hydrogen bond
with Y108, the phenyl ring inserts into a hydrophobic pocket
in the protein (Figure 3). To test our prediction, 5 was
* To whom correspondence should be addressed. Phone: 734-615-0362.
Fax: 734-647-9647. E-mail: shaomeng@umich.edu.
10.1021/jm701358v CCC: $40.75
2008 American Chemical Society
Published on Web 02/01/2008

718 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Letters
Scheme 2. Synthesis of Compounds 7-9a
Figure 3. Predicted binding models of Bcl-2 in complex with (a) 4
and 5, (b) 7 and 8, (c) 9, and (d) hMcl-1 and 9. Bcl-2 and hMcl-1 are
shown in surface representation where carbon, oxygen, nitrogen, and
sulfur atoms are in gray, red, blue, and orange, respectively. Carbon
and oxygen atoms in all designed compounds are in yellow and red,
respectively. The key residues in Bim BH3 peptide are shown and
labeled in light-blue and labeled in italic. Hydrogen bonds are depicted
as dashed lines in cyan.
a Reagents and conditions: (a) Br2 (1.1 equiv), AcOH, room temp, 1
day, 72%; (b) ethylene glycol (3 equiv), TsOH (cat.), toluene, Dean–Stark;
(c) n-BuLi (1.2 equiv), HMPA, THF, -78 °C, 0.5 h, then DMF, -78 °C
to room temp, 81%; (d) 4-phenoxyphenylmagnesium bromide (3.0 equiv),
THF, 0 °C to room temp, 3 h, 93%; (e) TsOH (cat.), acetone, 0 °C, 20
min, 86%; (f) RMgBr or RLi (3 equiv),THF, 0 °C, >82%; (g) Dess-Martin
periodinane (3.0 equiv), CH2Cl2, room temp, 40 min, >62%; (h) BBr3 (10
equiv), CH2Cl2, -78 to -20 °C, 6 h, >75%.
Scheme 1. Synthesis of Phenyl(2,3,4-trihydroxy-5-isopropyl-
phenyl)methanones 5 and 6a
showed that a phenoxy group on the para position of the phenyl
ring can occupy this hydrophobic pocket. We used an oxygen
linker between these two phenyl rings to balance the hydro-
phobic and hydrophilic properties of the resulting 6. Compound
6 was synthesized (Scheme 1) and determined to bind to Bcl-2
with an IC50 of 3.4 µM in the ELISA-based assay, being 11
times more potent than 5.
Modeling showed that the isopropyl group in 5 and 6 inserts
into the hydrophobic pocket occupied by Phe101 in the Bim
BH3 peptide (Figure 3), which can accommodate a larger
hydrophobic group than isopropyl for more optimal interaction.
To facilitate the synthesis of new analogues with larger
hydrophobic groups, we first designed and synthesized 7 (Figure
2) to test if insertion of a carbonyl group between the isopropyl
group and the pyrogallol core is tolerated. Compounds 6 and 7
were determined to have similar binding affinities to Bcl-2
(Figure 4), indicating that insertion of a carbonyl group at this
site is tolerated.
a Reagents and conditions: (a) t-BuLi (1.5 equiv), HMPA, THF, -78 to
-40 °C, then DMF, 91%; (b) substituted phenylmagnesium bromide, THF,
0 °C to room temp, 2 h, >90%; (c) Dess-Martin periodinane (1.5 equiv),
CH2Cl2, room temp, 30 min, >76%; (d) BBr3 (6 equiv), CH2Cl2, -78 to
-20 °C, >72%.
Compounds 8 and 9 were designed with a naphthyl or a
benzo[d]thiazolyl group to replace the isopropyl group in 7.
Modeling predicted that compared to 7, both 8 and 9 have an
improved hydrophobic interaction with Bcl-2. Compounds 8 and
9 were synthesized using a method similar to that used for 7
(Scheme 2). In the ELISA assay, 8 and 9 bind to Bcl-2 with
IC50 values of 0.29 and 0.17 µM, respectively, and are thus
9–15 times more potent than 7. Hence, 8 and 9 bind to Bcl-2
100-times more potently than the initial compound 5.
Recent studies have demonstrated that Mcl-1 can effectively
protect cancer cells from apoptosis induction when Bcl-2 and
Bcl-xL proteins are inhibited by ABT-737 (1), a potent and
specific inhibitor of Bcl-2 and Bcl-xL.23,24 Mcl-1 emerges as
an important and attractive molecular target for anticancer drug
design, independent of Bcl-2 and Bcl-xL proteins. We have thus
Figure 4. Competitive binding of 4-9 to Bcl-2 protein as determined
using an ELISA assay in competition with a biotinylated Bim peptide.
synthesized (Scheme 1). Compound 5 was determined to bind
to Bcl-2 with an IC50 of 41.6 µM in our ELISA-based binding
assay and is as potent as 4 (Figure 4).
Analysis of the predicted binding models of 5 and the Bim
BH3 peptide in a complex with Bcl-2 indicated that installation
of a hydrophobic group on the phenyl ring to interact with the
hydrophobic pocket occupied by Leu94 in the Bim BH3 peptide
could significantly enhance the binding affinity. Modeling

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 719
Figure 5. Competitive binding curves of designed compounds 5-9
to Mcl-1 protein as determined using a fluorescence-polarization assay.
Figure 7. Induction of apoptosis by 9 in the MDA-MB-231(2LMP)
breast cancer cell line and PC-3 prostate cancer cell line. Cells were
treated for 4 days, and apoptosis was analyzed by annexin-V/propidium
iodide staining by flow cytometry.
to the aldehyde 16 by a facile and quick deprotection with TsOH
in acetone. Alcohols 17a, 17b, and 17c were prepared by
addition of 16 to excess isopropylmagnesium chloride, 1-naph-
thylmagnesium bromide, and 2-benzothiazolyl lithium solution
prepared in situ, respectively. Oxidation of 17 with excess DMP
yielded the phenone 18. Demethylation of the trimethyl ethers
18a-c with BBr3 in DCM at -78 °C readily gave pyrogallols
7-9, respectively.
In summary, employing a structure-based strategy, we have
designed acylpyrogallols as new inhibitors of the antiapoptotic
Bcl-2 proteins. The most potent compound 9 binds to Bcl-2
and Mcl-1 with high affinities (IC50 ) 0.17 µM and Ki ) 37
nM, respectively). Consistent with its high binding affinities to
Bcl-2 and Mcl-1, 9 potently inhibits cell growth in the MDA-
MB-231 and PC-3 cancer cell lines with IC50 values of 120
and 260 nM, respectively, and effectively induces cell death
and apoptosis in these tumor cells. Compound 9 represents an
attractive lead compound for further optimization toward
development of a novel class of anticancer drugs aimed at
overcoming resistance of cancer cells to apoptosis.
Figure 6. Inhibition of cell growth by designed small molecules in
the MDA-MB-231(2LMP) breast cancer cell line and PC-3 prostate
cancer cell line. Cells were treated for 4 days, and cell growth was
determined by WST-based assay.
evaluated the binding affinities of 5-9 to Mcl-1 using our
established fluorescence-polarization (FP) assay.21 Compounds
5, 6, 7, 8, and 9 bind to Mcl-2 with Ki values of 4.6, 0.38, 0.34,
0.15, and 0.037 µM, respectively (Figure 5). We further
determined that 8 and 9 bind to Bcl-xL with Ki values of 1.32
and 1.11 µM, respectively, in our FP-based Bcl-xL assay.
Compounds 2 and 5-9 were tested for their activity in
inhibition of cell growth in the MDA-MB-231 (2LMP) human
breast cancer cell line and the PC-3 human prostate cancer cell
line, both of which express high levels of Bcl-2, Bcl-xL, and
Mcl-1 proteins (Supporting Information). Compounds 2, 5, 6,
7, 8, and 9 have IC50 values of 3.7, 30.7, 12.9, 4.5, 0.29, and
0.12 µM, respectively, in the MDA-MB-231 cell line and 2.5,
39.2, 12.4, 5.7, 0.55, and 0.26 µM, respectively, in the PC-3
cell line (Figure 6). Their potencies in inhibition of cancer cell
growth in both cell lines correlate well with their binding
affinities to Bcl-2 and Mcl-1 proteins.
We next evaluated the ability of 9 to induce apoptosis and
cell death in the MDA-MB-231 and PC-3 cancer cell lines
(Figure 6). Compound 9 effectively induced cell death in both
cancer cell lines in a time- and dose-dependent manner, as
determined using the trypan blue exclusion assay (Supporting
Information). For example, treatment with 9 at 0.3, 1, and 3
µM for 4 days induced 31 ( 3%, 58 ( 7%, and 86 ( 4% of
cells to undergo cell death in the MDA-MB-231 cancer cell
line (Supporting Information). Furthermore, 9 is very effective
in induction of apoptosis in the MDA-MB-231 and PC-3 cancer
cell lines, as shown by the Annexin-V/propidium iodide flow
cytometric analysis (Figure 7).
The synthesis of 5 and 6 is shown in Scheme 1. Briefly,
1-isopropyl-2,3,4-trimethoxybenzene was treated with tert-
butyllithium/HMPA and then DMF to give the benzaldehyde
10. Reaction of 10 with a Grignard reagent afforded a secondary
alcohol 11a or 11b, which was oxidized to the phenone 12a or
12b by excess Dess-Martin periodinane (DMP). The trimethyl
ether 12a or 12b was subjected to demethylation by BBr3 to
give the pyrogallol phenone 5 or 6.
The synthesis for 7-9 is shown in Scheme 2. 2,3,4-
Trimethoxybenzaldehyde was brominated by Br2 in AcOH to
give 13. The aldehyde group was protected as a 1,3-dioxolan,
and a second aldehyde group was added by n-BuLi and DMF
treatment to give 14. The 4-phenoxyphenyl group was incor-
porated to give the secondary alcohol 15, which was converted
Acknowledgment. We are grateful for the financial support
from the National Cancer Institute, National Institutes of Health
(Grant U19CA113317), the Department of Defense Breast
Cancer Program (Grant BC0009140), the Department of Defense
Prostate Cancer Program (Grant PC040537), the Prostate Cancer
Foundation, the Breast Cancer Research Foundation, the Susan
G. Komen Foundation, and Ascenta Therapeutics, Inc.
Supporting Information Available: An experimental section
including the chemical data for 5-9 and details of the fluorescence
polarization based and ELISA binding assays, molecular modeling,
and the cellular assays. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Nicholson, D. W. From bench to clinic with apoptosis-based thera-
peutic agents. Nature 2000, 407, 810–816.
(2) Lowe, S. W.; Lin, A. W. Apoptosis in cancer. Carcinogenesis 2000,
21, 485–495.
(3) Ponder, B. A. Cancer genetics. Nature 2001, 411, 336–341.
(4) Adams, J. M.; Cory, S. The Bcl-2 protein family: arbiters of cell
survival. Science 1998, 281, 1322–1326.
(5) Reed, J. C. Bcl-2 family proteins: strategies for overcoming chemore-
sistance in cancer. AdV. Pharmacol. 1997, 41, 501–553.
(6) Chao, D. T.; Korsmeyer, S. J. Bcl-2 family: regulators of cell death.
Annu. ReV. Immunol. 1998, 16, 395–419.
(7) Minn, A. J.; Swain, R. E.; Ma, A.; Thompson, C. B. Recent progress
on the regulation of apoptosis by bcl-2 family members. AdVances in
Immunology 1998, 70, 245–279.
(8) Willis, S. N.; Fletcher, J. I.; Kaufmann, T.; van Delft, M. F.; Chen,
L.; Czabotar, P. E.; Ierino, H.; Lee, E. F.; Fairlie, W. D.; Bouillet, P.;
Strasser, A.; Kluck, R. M.; Adams, J. M.; Huang, D. C. Apoptosis
initiated when BH3 ligands engage multiple Bcl-2 homologs. not Bax
or Bak. Science 2007, 315, 856–9.

720 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Letters
(9) Petros, A. M.; Medek, A.; Nettesheim, D. G.; Kim, D. H.; Yoon, H. S.;
Swift, K.; Matayoshi, E. D.; Oltersdorf, T.; Fesik, S. W. Solution
structure of the antiapoptotic protein Bcl-2. Proc. Natl. Acad. Sci. USA,
2001, 98, 3012–3017.
(10) Sattler, M.; Liang, H.; Nettesheim, D.; Meadows, R. P.; Harlan, J. E.;
Eberstadt, M.; Yoon, H. S.; Shuker, S. B.; Chang, B. S.; Minn, A. J.;
Thompson, C. B. Fesik. S. W. Structure of Bcl-xL-Bak peptide complex:
recognition between regulators of apoptosis. Science 1997, 275, 983–
986.
(11) Petros, A. M.; Nettesheim, D. G.; Wang, Y.; Olejniczak, E. T.;
Meadows, R. P.; Mack, J.; Swift, K.; Matayoshi, E. D.; Zhang, H.;
Thompson, C. B.; Fesik, S. W. Rationale for Bcl-xL/Bad peptide
complex formation from structure. mutagenesis, and biophysical
studies. Protein Sci. 2000, 9, 2528–2534.
(12) Wang, J. L.; Liu, D.; Zhang, Z. J.; Shan, S.; Han, X.; Srinivasula,
S. M.; Croce, C. M.; Alnemri, E. S.; Huang, Z. Structure-based
discovery of an organic compound that binds Bcl-2 protein and induces
apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2000, 97, 7124–
7129.
(13) Degterev, A.; Lugovskoy, A.; Cardone, M.; Mulley, B.; Wagner, G.;
Mitchison, T.; Yuan, J. Identification of small-molecule inhibitors of
interaction between the BH3 domain and Bcl-xL. Nat. Cell Biol. 2001,
3, 173–182.
(14) Tzung, S. P.; Kim, K. M.; Basanez, G.; Giedt, C. D.; Simon, J.;
Zimmerberg, J.; Zhang, K. Y.; Hockenbery, D. M. Antimycin A
mimics a cell-death-inducing Bcl-2 homology domain 3. Nat. Cell
Biol. 2001, 3, 183–91.
(15) Enyedy, I. J.; Ling, Y.; Nacro, K.; Tomita, Y.; Wu, X.; Cao, Y.; Guo,
R.; Li, B.; Zhu, X.; Huang, Y.; Long, Y. Q.; Roller, P. P.; Yang, D.;
Wang, S. Discovery of small-molecule inhibitors of Bcl-2 through
structure-based computer screening. J. Med. Chem. 2001, 44, 4313–
4324.
(16) Kitada, S.; Leone, M.; Sareth, S.; Zhai, D.; Reed, J. C.; Pellecchia,
M. Discovery, characterization, and structure-activity relationships
studies of proapoptotic polyphenols targeting B-Cell lymphocyte/
leukemia-2 proteins. J. Med. Chem. 2003, 46, 4259–4264.
(17) Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.;
Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges,
J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer,
A. R.; Letai, A.; Li, C.; Mitten, M. J.; Nettesheim, D. G.; Ng, S.;
Nimmer, P. M.; O’Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed,
J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang,
B.; Wendt, M. D.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H. An
inhibitor of Bcl-2 family proteins induces regression of solid tumours.
Nature 2005, 435, 677–81.
(18) Petros, A. M.; Dinges, J.; Augeri, D. J.; Baumeister, S. A.; Betebenner,
D. A.; Bures, M. G.; Elmore, S. W.; Hajduk, P. J.; Joseph, M. K.;
Landis, S. K.; Nettesheim, D. G.; Rosenberg, S. H.; Shen, W.; Thomas,
S.; Wang, X.; Zanze, I.; Zhang, H.; Fesik, S. W. Discovery of a potent
inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel
synthesis, Discovery of a potent inhibitor of the antiapoptotic protein
Bcl-xL from NMR and parallel synthesis. J. Med. Chem. 2006, 49,
656–63.
(19) Bruncko, M.; Oost, T. K.; Belli, B. A.; Ding, H.; Joseph, M. K.;
Kunzer, A.; Martineau, D.; McClellan, W. J.; Mitten, M.; Ng, S.-C.;
Nimmer, P. M.; Oltersdorf, T.; Park, C.-M.; Petros, A. M.; Shoemaker,
A. R.; Song, X.; Wang, X.; Wendt, M. D.; Zhang, H.; Fesik, S. W.;
Rosenberg, S. H.; Elmore, S. W. Studies leading to potent, dual
inhibitors of Bcl-2 and Bcl-xL. J. Med. Chem. 2007, 50, 641–662.
(20) Wang, G.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Wang, R.; Tang, G.;
Guo, J.; Shangary, S.; Qiu, S.; Gao, W.; Yang, D.; Meagher, J.;
Stuckey, J.; Krajewski, K.; Jiang, S.; Roller, P. P.; Abaan, H. O.;
Tomita, Y.; Wang, S. Structure-Based Design of Potent Small-
Molecule Inhibitors of Anti-Apoptotic Bcl-2 Proteins. J. Med. Chem.
2006, 49, 6139–6142.
(21) Tang, G.; Yang, C.-Y.; Nikolovska-Coleska, Z.; Guo, J.; Qiu, S.; Wang,
R.; Gao, W.; Wang, G.; Stuckey, J.; Krajewski, K.; Jiang, S.; Roller,
P. P.; Wang, S. Pyrogallol-based molecules as potent inhibitors of
the antiapoptotic Bcl-2 proteins. J. Med. Chem. 2007, 50, 1723–1726.
(22) Tang, G.; Ding, K.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Qiu, S.;
Shangary, S.; Wang, R.; Guo, J.; Gao, W.; Meagher, J.; Stuckey, J.;
Krajewski, K.; Jiang, S.; Roller, P. P.; Wang, S. Structure-based design
of flavonoid compounds as a new class of small-molecule inhibitors
of the anti-apoptotic Bcl-2 proteins. J. Med. Chem. 2007, 50, 3163–
3166.
(23) Konopleva, M.; Contractor, R.; Tsao, T.; Samudio, I.; Ruvolo, P. P.;
Kitada, S.; Deng, X.; Zhai, D.; Shi, Y. X.; Sneed, T.; Verhaegen, M.;
Soengas, M.; Ruvolo, V. R.; McQueen, T.; Schober, W. D.; Watt,
J. C.; Jiffar, T.; Ling, X.; Marini, F. C.; Harris, D.; Dietrich, M.; Estrov,
Z.; McCubrey, J.; May, W.S.; Reed, J. C.; Andreeff, M. Mechanisms
of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737
in acute myeloid leukemia. Cancer Cell. 2006, 10, 375–88.
(24) van Delft, M. F.; Wei, A. H.; Mason, K. D.; Vandenberg, C. J.; Chen,
L.; Czabotar, P. E.; Willis, S. N.; Scott, C. L.; Day, C. L.; Cory, S.;
Adams, J. M.; Roberts, A. W.; Huang, D. C. The BH3 mimetic ABT-
737 targets selective Bcl-2 proteins and efficiently induces apoptosis
Via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006, 10, 389–99.
JM701358V