Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)

Article abstract of DOI:10.1016/j.bmcl.2016.10.087

Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

Full text of DOI:10.1016/j.bmcl.2016.10.087

Accepted Manuscript
Discovery of TAK-659 an Orally Available Investigational Inhibitor of Spleen
Tyrosine Kinase (SYK)
Betty Lam, Yasuyoshi Arikawa, Joshua Cramlett, Qing Dong, Ron de Jong,
Victoria Feher, Charles E. Grimshaw, Pamela J. Farrell, Isaac D. Hoffman, Andy
Jennings, Benjamin Jones, Jennifer Matuszkiewicz, Joanne Miura, Hiroshi
Miyake, Srinivasa Reddy Natala, Lihong Shi, Masashi Takahashi, Ewan Taylor,
Corey Wyrick, Jason Yano, Jonathan Zalevsky, Zhe Nie
PII:
S0960-894X(16)31135-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.10.087
BMCL 24390
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 October 2016
26 October 2016
28 October 2016
Please cite this article as: Lam, B., Arikawa, Y., Cramlett, J., Dong, Q., de Jong, R., Feher, V., Grimshaw, C.E.,
Farrell, P.J., Hoffman, I.D., Jennings, A., Jones, B., Matuszkiewicz, J., Miura, J., Miyake, H., Natala, S.R., Shi, L.,
Takahashi, M., Taylor, E., Wyrick, C., Yano, J., Zalevsky, J., Nie, Z., Discovery of TAK-659 an Orally Available
Investigational Inhibitor of Spleen Tyrosine Kinase (SYK), Bioorganic & Medicinal Chemistry Letters (2016), doi:
http://dx.doi.org/10.1016/j.bmcl.2016.10.087
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Discovery of TAK-659 an Orally Available
Investigational Inhibitor of Spleen Tyrosine
Kinase (SYK)
Leave this area blank for abstract info.
Betty Lam*, Yasuyoshi Arikawa, Joshua Cramlett, Qing Dong, Ron de Jong, Victoria Feher Charles E.
Grimshaw, Pamela J. Farrell, Isaac D. Hoffman, Andy Jennings, Benjamin Jones, Jennifer Matuszkiewicz,
Joanne Miura, Hiroshi Miyake, Srinivasa Reddy Natala, Lihong Shi, Masashi Takahashi, Ewan Taylor, Corey
Wyrick, Jason Yano, Jonathan Zalevsky, and Zhe Nie

Bioorganic & Medicinal Chemistry Letters
Discovery of TAK-659 an Orally Available Investigational Inhibitor of Spleen
Tyrosine Kinase (SYK)
a,
b
c
d
a
e
Betty Lam *, Yasuyoshi Arikawa , Joshua Cramlett , Qing Dong , Ron de Jong , Victoria Feher , Charles E.
a
a
a
a
a
f
Grimshaw , Pamela J. Farrell , Isaac D. Hoffman , Andy Jennings , Benjamin Jones , Jennifer Matuszkiewicz ,
a
b
g
f
b
a
Joanne Miura , Hiroshi Miyake , Srinivasa Reddy Natala , Lihong Shi , Masashi Takahashi , Ewan Taylor ,
Corey Wyrick a, Jason Yano h, Jonathan Zalevsky i and Zhe Nie f
a Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA
bTakeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
cPolyScientific Consulting Inc. 4624 Aragon Dr, San Diego, CA 92115
dFronThera US Pharmaceuticals, 11526 Sorrento Valley Road, Suite D, San Diego, CA92121
eSchrödinger, Inc. 5820 Oberlin Drive, Ste. 203, San Diego, CA 92121
fCelgene Quanticel Research, 9393 Towne Center Drive, Suite 110, San Diego, California 92121, USA
gNeuropore Therapies, 10835 Road to Cure, Suite 230 San Diego, CA 92121
hBeryllium Discovery, 3 Preston Ct., Bedford, MA 01730
iNektar Therapeutics, 455 Mission Bay Boulevard South San Francisco, CA 94158
ABSTRACT
ARTICLE INFO
Article history:
Received
Revised
Accepted
Available online
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily
expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells,
including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach
for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal
structure information, and structure-based drug design, we designed and optimized a novel series
of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development
candidate TAK−659. TAK−659 is currently undergoing Phase I clinical trials for advanced
solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in
combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.
2016 Elsevier Ltd. All rights reserved.
Keywords:
SYK
Kinase inhibitor
Kinase selectivity
Structure-based drug discovery
Leukemia
Lymphoma
Spleen Tyrosine Kinase (SYK) is a 72 kD non-receptor
cytoplasmic tyrosine kinase that is primarily expressed in
hematopoietic cells. SYK is a key mediator for a variety of
inflammatory cells and immunology signaling pathways,
including B cell receptor (BCR) in B cells, FcR in lymphoid and
myeloid cells, and FcRI in mast cells, basophils, and
neutrophils.1a-f Recent studies have implicated abnormal SYK
activation in several hematopoietic malignancies including
chronic lymphocytic leukemia (CLL), peripheral T-cell
lymphoma (PTCL), acute myeloid leukemia (AML) and diffuse
large B-cell lymphoma (DLBCL).2a-c Research has also identified
an oncogenic collaboration between SYK and FMS-like tyrosine
kinase 3 (FLT3) in AML. In addition, activating mutations within
the FLT3 gene on chromosome 13q12 have been detected in
approximately 30% of AML patients and accounted for one of
the most frequently identified genetic alterations in AML.3a-b
Internal tandem duplication (ITD) of the FLT3 gene, occurs at
high frequency in AML and SYK, is critical for the development
of FLT3-ITD-induced myeloid neoplasia since it is more highly
activated in primary human FLT3-ITD-positive AML than its
FLT3 wild-type (WT) AML counterparts, and moreover
transactivates FLT3 by direct phosphorylation.4a-e Hence, SYK
inhibition provides a desirable mechanistic intervention for
potential treatment of inflammatory diseases and oncology
indications.
In recent years, a number of SYK inhibitors have advanced to
clinical trials for inflammatory disease indications, such as
asthma, arthritis and allergic diseases.5 Most have been
terminated in Phase I/II studies due to various reasons. An
example is fostamatinib (R–788). Fostamatinib showed
promising Phase I results in patients with rheumatoid arthritis,
however little efficacy was observed in Phase II studies.6a-b When
dosed at 150mg BID, patients were experiencing adverse events,
such as diarrhea, upper respiratory tract infections, neutropenia,
elevated alanine transaminase (ALT), and hypertension.
Fostamatinib is a non-selective SYK inhibitor, thus the observed
undesirable side effects were hypothesized to be caused by off-
target inhibition.7a-b In the past, generation of selective SYK
inhibitors has been challenging,5,7c,d however, as shown in this
article, we succeeded in the design of highly selective SYK
compounds by utilizing structure-based drug design (SBDD).
Herein we report the discovery of TAK−659, a potent and
selective SYK inhibitor that is currently undergoing Phase Ib/II
evaluations in adult patients with solid tumors and hematologic
malignancies.

Supported by high-throughput protein crystallization techno-
logy and applying SBDD strategy, we had designed a novel
series of dihydropyrrolopyrimidinone SYK inhibitors, which led
to the discovery of our first lead compound, compound 1. A co-
crystal structure of compound 1 in the SYK active site8 was
obtained (Figure 1). Compound 1 binds to the hinge region of
SYK which adopts the active DFG-in (Phe513) conformation.
The lactam core makes two direct hydrogen bonds (HBs) with
the hinge through Ala451, and Glu449. Multiple interactions are
observed between the primary and secondary amines of the
cyclohexyl ring with the polar region comprised of Arg498,
Asn499, and Asp512. One of the pyrimidine ring nitrogen atoms
forms a water mediated HB (HOH136; cyan) with Ser511.
Leu377 and Pro455 provide a lipophilic pocket for the m-methyl
aniline ring of compound 1.
different R groups increased both enzyme (3 to 26–fold) and
cellular potency (7 to >12–fold), while kinase selectivity was
compromised. Most of these compounds inhibited CYPs, with
the exception of compound 2b. Although compound 2b showed
improved enzyme and cellular potency, was selective against
JAK3 (170–fold selective compared to SYK potency) and had no
CYPs liability, further study showed that it inhibited hERG. To
mitigate the hERG liability and remove the problematic aniline
group, a number of aniline mimetics were synthesized. As shown
in Table 2, the cyclized pyrazolopyridine compound 3a, retained
both enzyme and cellular potency, possessed improved kinase
selectivity, and did not inhibit CYPs. Upon further optimization
by lowering molecular weight and cLogP, and improving LipE,
compound 3b, with methylpyrazole, was identified. Compound
3b had a good in vitro profile, did not have CYP or hERG
liabilities, and had become our drug candidate TAK−659
The synthesis of compound 3a and TAK−659 was performed
according to the method depicted in Scheme 3.10 2,6-dichloro-5-
fluoronicotinic acid was lithiated via treatment with LDA in THF
at -78°C. Quenching with DMF gave hemiacetal intermediate 5,
which underwent reductive amination through reaction with (2,4-
dimethoxyphenyl)methanamine) and NaBH3CN. The resulting
amino acid (not shown) was cyclized via amide coupling to form
the lactam ring. Displacement of the chloro group of intermediate
6 with commercially available tert-butyl (lS, 2R)-2-amino-
cyclohexyl-carbamate9b was followed by Suzuki coupling with
pyrazolo [1, 5-a] pyridin-3-ylboronic acid or (1-methyl-1H-
pyrazol -4-yl) boronic acid, respectively. Final Boc deprotection
of 7 afforded compounds 3a and TAK−659.
Figure 1. Co-crystal structure of compound 1 in the SYK active site.
While compound 1 (see Scheme 1 in supplemental data for
synthesis)9a is an efficient and potent inhibitor of SYK (IC50 = 13
nM ; LE = 0.41; LipE = 4.3), its cellular potency as measured by
inhibition of phosphorylation of BLNK, a direct cellular substrate
of SYK,10 and selectivity toward JAK3 were not optimal. It also
had hERG and CYP liabilities (Figure 2). Our goals for lead
optimization were to improve cellular potency and JAK3
selectivity, reduce inhibitions toward CYPs and hERG, and
replace the aniline group, which is a known toxicophore that can
potentially form reactive metabolites.
SYK IC
Cell1 EC
13 nM
35 nM
50
Figure 3. Co-crystal structure of compound TAK−659in the SYK active site. C5-F
displaced the HOH136 normally found bound between the core N and the backbone of
Asp512.
50
Kinase
JAK3
ZAP70
VEGFR2
Fold-Selectivity
19
21
250
7.9 M
3.6
0.41
4.3
0.25
Shown in Figure 3 is a co-crystal structure of TAK−659 in
the SYK active site that was solved at 1.93 Å. TAK−659
maintains all key interactions with the SYK active site. For
example, the HBs between the lactam core and the hinge through
Ala451 and Glu449, the methyl pyrazole ring occupying the
lipophilic region with one of the nitrogens forming an HB with a
water molecule, multiple interactions between the primary and
secondary amines of the cyclohexyl ring with the polar region
comprised of Arg498, Asn499, and Asp512, and the C5-F
substituent disrupting the water-mediated network by displacing
HOH136 (cyan).
CYP (2D6)
cLogP
LE2
LipE3
E (HLM)10
h
hERG
41%@10M
1
2
*
*
Cellular BLNK phosphorylation inhibition
Ligand efficiency (LE): 1.4(-logIC50)/N
3Lipophilic Efficiency (LipE) = LipE = pIC50 - LogP
Human liver microsomes extraction ration: Eh(HLM)
Figure 2. Chemical and physical properties of compound 1.
One way to improve potency and selectivity was to disrupt the
water-mediated HB between the pyrimidine nitrogen and Ser511.
Since water HOH136 was not a structural water, replacing it
should be entropically beneficial to enhance potency. From SAR
development (Table 1, and Scheme 2 in supplemental for
syntheses of compound 2a−f),10 displacement of the water with
280 kinases screened in house and at Invitrogen/Life
Technologies showed that TAK−659 was selective against most
other kinases, but retained potency towards both SYK and FLT3
(Tables 3−6).10 In a cell proliferation assay, TAK−659 showed
inhibition towards a SYK-dependent cell line (OCI-LY10).11 The

result demonstrated that the sensitivity to TAK−659 was
associated with mutations impacting SYK activity in B cell
lymphomas, whereas TAK−659 was not cytotoxic for adherent
primary or solid tumor cell lines. In cell viability assays (Figure
4 in supplemental data), TAK−659 was shown to be sensitive
toward FLT3-ITD dependent cell lines, MV4-11 and MOLM-13
while the WT FLT3 RS4-11 (ALL cell line) and RA1 (Burkitt's
Lymphoma cell line) are not sensitive towards TAK−659. To
evaluate SYK inhibition in vivo in a pre-clinical immunology
model, TAK−659 was tested against an in vivo C57BL/6 mouse
whole blood assay (Figure 5 in supplemental data). The purpose
of this assay was to evaluate CD86 (cluster of differentiation 86)
expression after primary B-cell activation which was dependent
on SYK activity. The result showed that TAK−659 blocks anti-
IgD (immune-globulin D antibody) stimulated CD86 expression
in mouse peripheral B cells in vivo.
Table 1. Structure-activity relationship of R substituents on compound 1. Cell EC50 represents cellular p-BLNK inhibition in RA1/GFP-BLNK cells.
2a
H
2b
F
2c
Cl
2d
Me
2e
CN
2f
R
4.7
5
1.1
9
0.8
NT
3.1
NT
0.5
< 3
0.9
4
SYK IC50 (nM)
Cell EC50 (nM)
Fold-Selectivity against individual SYK potency
70
23
260
170
29
590
53
19
NT
18
9
NT
3.3
3.5
1,800
10
0.5
220
JAK3
ZAP70
VEGFR2
No
4.1
4.2
Yes
4.3
4.7
No
4.7
4.4
No
4.6
3.9
No
3.9
5.4
No
4.1
5.0
CYPs (>10 M)
cLogP
LipE
Table 2. Lead optimization and discovery of TAK−659
3b (TAK−659)
2b
1.1
9
3a
2.3
9
3.2
9.8
SYK IC50 (nM)
Cell EC50 (nM)
Fold-Selectivity against individual SYK potency
170
29
590
260
170
2800
36
23
42
JAK3
ZAP70
VEGFR2

4.3
4.7


0.9
7.5
CYPs ( >10 M)
cLogP
LipE
hERG (10M)
2.0
6.7
NT
47%
<10%
Scheme 3. Reagents and conditions: (a) LDA, -78ºC, DMF/THF, 1h, 80%; (b) (2,4-dimethoxyphenyl)methanamine, NaBH3CN, AcOH, MeOH, rt, 4h, 74%; (c) EDC, HOBt, DMF, 2h,
90%; (d) tert-butyl (lS,2R)-2-amino-cyclohexylcarbamate, DIEA, ACN, 100°C, 2-4 days, 40%; (e) for R1 = 3a: pyrazolo[1,5-a]pyridin-3-ylboronic acid; for R1 = 3b: (1-methyl-1H-
pyrazol-4-yl)boronic acid, Pd(PPh3)2Cl2, Na2CO3, DME-H2O, 100°C, o/n, 68%; (f) neat TFA, 60°C, 2h, 79%

Puissant, A.; Fenouille, N.; Alexe, G.; Pikman, Y.; Bassil, C.F.; Mehta,
S.; Du, J.; Kazi, J.U.; Luciano, F.; Rönnstrand, L.; Kung, A.L.; Aster,
J.C.; Galinsky, I.; Stone, R.M.; DeAngelo, D.J.; Hemann, M.T.;
Stegmaier, K.; Cancer Cell, 2014 Feb 10, 25, 2, 226–242. (d) Pratz, K.;
Levis, M.; Leuk Lymphoma, 2008 May, 49, 5, 852–863. (e) Hahn,
C.K.; Berchuck, J.E.; Ross, K.N.; Kakoza, R.M.; Clauser, K.; Schinzel,
A.C.; Ross, L.; Galinsky, I.; Davis, T.N.; Silver, S.J.; Root, D.E.;
Stone, R.M.; DeAngelo, D.J.; Carroll, M.; Hahn, W.C.; Carr, S.A.;
Golub, T.R.; Kung, A.L.; Stegmaier, K.; Cancer Cell, 2009 Oct 6, 16,
4, 281–294
Assessment of tumor growth inhibition in the OCI-LY10
xenograft and DLBCL PHTX-95L (primary human tumor graft
from DLBCL patient) mouse models, TAK−659 demonstrates
potent tumor growth inhibition (TGI) after 20 days of treatment.
11
In the FLT3-dependent MV4-11 xenograft model, TAK−659
showed tumor regression at 60 mg/kg daily after 20 days of
dosing.10
In conclusion, we have utilized high-throughput protein
crystallography and SBDD to design a novel series of SYK
inhibitors, which facilitated in the discovery and optimization of
5.
6.
Norman, P., Espert Opin. Ther. Patents, 2014, 24, 5, 573-595.
(a) Lucas, M.C.; Tan, S. L.; Future Med. Chem., 2014, 6, 16, 1811-
1827. (b) AstraZeneca announces top-line results from Phase
3
OSKIRA Trials of FOSTAMATINIB and decision not to proceed with
regulatory filings. Press Release, Tuesday, 4 June 2013.
a
potent and selective dihydropyrrolopyrimidinone lead
compound 1. Displacement of water in the SYK active site
enhanced potency and selectivity against JAK3, and replace-
ment of the aniline and lowering of cLogP reduced hERG and
reactive metabolite risk, which led to the discovery of
TAK−659. TAK−659 inhibits cellular proliferation in SYK-
dependent DLBCL and FLT3-dependent AML cell lines, and
shows notable TGI in SYK- and FLT3-dependent xenograft
models. Clinical trials of TAK−659 for the treatment of
advanced solid tumors and lymphoma malignancies are
ongoing.12-13
7.
(a) Weinblatt, M. E.; Kavanaugh, A.; Genovese, M.C.; Jones, D.A.;
Musser, T.K.; Grossbard, E.B.; Magilav, D.B.; J Rheumatol, 2013, 40,
4, 369-78. (b) Weinblatt , M.E.; Kavanaugh , A. ; Burgos-Vargas, R.;
Dikranian, A.H.; Medrano-Ramirez, G.; Morales-Torres, J.L.; Murphy,
F.T.; Musser, T.K.; Straniero, N.; Vicente-Gonzales, A.V.; Grossbard,
E.; Arthritis Rheum. 2008 Nov, 58, 11, 3309-18. (c) Moretto, A.F.;
Dehnhardt, C.; Kaila, N.; Papaioannou, N.; Thorarensen, A.; Recent
Patents on Inflammation & Allergy Drug Discovery 2012, 6, 97-120.
(d) Thoma, G.; Blanz, J.; Bühlmayer, P.; Drückes, P.; Kittelmann, M.;
Smith, A.B.; Van Eis, M.; Vangrevelinghe, E.; Zerwes, H.; Che, J.; He,
X.; Jin, Y.; Lee, C.C.; Michellys, P.; Uno, T.; Liu, H.; Bioorg. Med.
Chem. Lett. 2014, 24, 2278–2282
8.
9.
Protein Data Bank code: will be provided upon acceptance of the paper
for publication.
Acknowledgements:
(a). Full experimental procedures for all syntheses are contained within
the following patent: Arikawa, Y.; Jones, B.; Lam, B.; Nie, Z.; Smith,
C.; Takahashi, M.; Dong, Q.; Feher, V.. Patent No.: WO/2011/079051
A1. US20110152273 A1, 2011. (b). Optically pure tert-butyl (lS,2R)-
2-amino-cyclohexyl-carbamate is commercially available from Aldrich
and TCI-US, etc.
We acknowledge the ADME group for generating the micro-
somal and solubility data, and the cellular pharmacology group
for generating cellular data. The X-ray crystallography data
reported here are based on research conducted at the Advanced
Light Source (ALS). ALS is supported by the Director, Office of
Science, Office of Basic Energy Sciences, Materials Sciences
Division, of the U.S. Department of Energy under Contract No.
DE-AC03-76SF00098 at the Lawrence Berkeley National
Laboratory. We thank the staff at ALS for their excellent support
in the use of the synchrotron beamlines. The authors express their
appreciation to Ron Chen, Gavin Hirst, Shota Kikuchi, Beverly
Knight, Mitsunori Kouno, Matt Lardy, Sean Murphy, Lisa
Rahbaek, Chris Smith, and Gyorgy Snell for their drug discovery
advice.
10. Supplemental Data:
11. Huck, J., et al. Antitumor activity of inhibiting SYK kinase with
TAK−659, an investigational agent, in DLBCL models. Presented at
2014 American Society Of Clinical Oncology Annual Meeting;
Chicago, Illinois. Abstract No: 8580
12. (a). Petrich, A.M.; Gordon, L.I.; Infante, J.R., et al. Ongoing, first-in-
human, phase 1 dose-escalation study of investigational SYK inhibitor
TAK−659 in patients with advanced solid tumors or lymphoma.
Presented at: 13th International Conference on Malignant Lymphoma,
2015; Lugano, Switzerland. Abstract 039. (b). Petrich, A.M.; Gordon,
L.I.; Infante, J.R.; Madan, S.; Giles, F.J.; Nimeiri, H.S.; Kaplan, J.B.;
Stumpo, K.: Zhang, B.; Faucette, S.; Shou, Y.; Shih, K.C.; 2693 Phase
1
Dose-Escalation Study of TAK−659, an Investigational SYK
Inhibitor, in Patients (Pts) with Advanced Solid Tumor or Lymphoma
Malignancies. Presented at: 57th American Society of Hematology
Annual Meeting, 2015; Orlando, Florida. Lymphoma: Chemotherapy,
excluding Pre-Clinical Models; Program: Oral and Poster Abstracts;
Session: 623. Lymphoma: Chemotherapy, excluding Pre-Clinical
Models: Poster II. (c). Lam, B.; MEDI 30: Discovery of TAK−659, An
Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase
(SYK). Presented at 250th American Chemical Society National
Meeting & Exposition, 2015. Boston, USA
References and notes:
1.
(a) Sada K.; Takano T.; Yamamura, H.; J Biochem 2001, 130, 2, 177-
186. (b) Wong, B.R.; Grossbard, E.B.; Payan, D.G.; Masuda, E.S.;
Expert Opin. Inestig. Drug, 2004, 13, 7, 743-762. (c) Bogusz, A.M.;
Baxter, R.H.; Currie, T.; Sinha, P.; Sohani, A.R.; Kutok, J.L.; Rodig,
S.J.; Clin Cancer Res. 2012 Nov 15, 18, 22, 6122-35. (d) Chen, L.;
Monti, S,; Juszczynski, P.; Daley, J.; Chen, W.; Witzig, T.E.;
Habermann, T.M.; Kutok, J.L.; Shipp, M.A.; Blood, 2008 Feb 15, 111,
4, 2230-7. (e) Cheng, S.; Coffey, G.; Zhang, X.H.; Shaknovich, R.;
Song, Z.; Lu, P.; Pandey, A.; Melnick, A.M.; Sinha, U.; Wang, Y.L.;
Blood, 2011, 118, 24, 6342–52. (f) Davis, R.E.; Ngo, V.N.; Lenz, G.;
Tolar, P.; Young, R.M.; Romesser, P.B.; Kohlhammer, H.; Lamy, L.;
Zhao, H.; Yang, Y.; Xu, W.; Shaffer, A.L.; Wright, G.; Xiao, W.;
Powell, J.; Jiang, J.K.; Thomas, C.J.; Rosenwald, A.; Ott, G.; Muller-
Hermelink, H.K.; Gascoyne, R.D.; Connors, J.M.; Johnson, N.A.;
Rimsza, L.M.; Campo, E.; Jaffe, E.S.; Wilson, W.H.; Delabie, J.;
Smeland, E.B.; Fisher, R.I.; Braziel, R.M.; Tubbs, R.R.; Cook, J.R.;
Weisenburger, D.D.; Chan, W.C.; Pierce, S.K.; Staudt, L.M.; Nature,
2010, 463, 7277, 88–92
13. Takeda global site disclosed TAK−659 entering Phase Ib/II clinical
trial for solid tumors and hematological malignancies. May, 2014. Also
obtained latest results from www.clinicaltrials.gov
2.
3.
(a) Davis, R.E., et al. Nature 2010, 463, 7277, 88–92. (b) Efremov,
D.G.; Laurenti, L.; Expert Opin Investig Drugs. 2011, 20, 5, 623–36.
(c) Knapper, S.; Expert Opin Investig Drugs, 2011, 20, 10, 1377-95;
(a) Zarrinkar, P.P.; Gunawardane, R.N.; Cramer, M.D.; Gardner, M.F.;
Brigham,D.; Belli, B.; Karaman, M.W.; Pratz, K.W.; Pallares, G.;
Chao, Q.; Sprankle, K.G.; Patel, H.K.; Levis, M.; Armstrong, R.C.;
James, J.; Bhagwat, S.S; Blood, 2009 Oct 1, 114, 14,2984–92. (b)
Levis, M.; Small, D.; Leukemia, 2003, 17, 1738–1752. (c) Kindler, T.;
Lipka, D.B.; Fischer, T.; Blood, 2010 Dec 9; 116(24):5089-102
(a). Stirewalt, D.L.; Kopecky, K.J.; Meshinchi, S.; Engel, J.H.;
Pogosova-Agadjanyan, E.L.; Linsley, J.; Slovak, M.L.; Willman, C.L.;
Radich, J.P.; Blood, 2006 May 1, 107, 9, 3724-26. (b) Kottaridis, P.D.;
Gale, R.E.; Frew, M.E.; Harrison, G.; Langabeer, S.E.; Belton, A.A.;
Walker, H.; Wheatley, K.; Bowen, D.T.; Burnett, A.K.; Goldstone,
A.H.; Linch, D.C.; Blood, 2001 September 15, 98, 6, 1725-59. (c)
4.