| Reference | 1. Anticancer Res. 2017 Feb;37(2):437-444. <br />
Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active
BAX in Cancer Cells. <br />
Murai S(1), Matuszkiewicz J(2), Okuzono Y(3), Miya H(3), DE Jong R(4). <br />
Author information: <br />
(1)Pharmacology Research Laboratory II, Pharmaceutical Research Laboratories,
Takeda Pharmaceutical Company Ltd., Kanagawa, Japan [email protected]
[email protected].
(2)Discovery Biology, Takeda California, Inc., San Diego, CA, U.S.A.
(3)Pharmacology Research Laboratory II, Pharmaceutical Research Laboratories,
Takeda Pharmaceutical Company Ltd., Kanagawa, Japan.
(4)Discovery Biology, Takeda California, Inc., San Diego, CA, U.S.A.
[email protected] [email protected]. <br />
BACKGROUND: Aurora B kinase plays an essential role in chromosome segregation and
cytokinesis, and is dysregulated in many cancer types, making it an attractive
therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy
in both in vitro and in vivo oncology models.<br />
MATERIALS AND METHODS: We conducted a synthetic lethal siRNA screening to
identify the genes that, when silenced, can potentiate the cell growth-inhibitory
effect of TAK-901.<br />
RESULTS: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical
inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of
synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was
induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis
induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition.<br />
CONCLUSION: Polyploid cells induced by TAK-901 are vulnerable to BCL-xL
inhibition. Our findings may have an impact on combination strategies with aurora
B inhibitors in clinical studies. <br />
2. Nucl Med Biol. 2014 Feb;41(2):148-54. doi: 10.1016/j.nucmedbio.2013.11.001. Epub
2013 Nov 15. <br />
Preclinical FLT-PET and FDG-PET imaging of tumor response to the multi-targeted
Aurora B kinase inhibitor, TAK-901. <br />
Cullinane C(1), Waldeck KL(2), Binns D(3), Bogatyreva E(2), Bradley DP(4), de
Jong R(5), McArthur GA(6), Hicks RJ(7). <br />
Author information: <br />
(1)Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University
of Melbourne, Parkville, Victoria, Australia. Electronic address:
[email protected].
(2)Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia.
(3)Centre for Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia.
(4)Millennium Pharmaceuticals, Cambridge, MA.
(5)Takeda California, San Diego, CA.
(6)Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia; Division of Cancer Medicine, Peter MacCallum Cancer Centre,
East Melbourne, Victoria, Australia; Department of Medicine, St Vincent/’s
Hospital, The University of Melbourne, Parkville, Victoria, Australia; Sir Peter
MacCallum Department of Oncology, The University of Melbourne, Parkville,
Victoria, Australia.
(7)Division of Cancer Research, Peter MacCallum Cancer Centre, East Melbourne,
Victoria, Australia; Centre for Cancer Imaging, Peter MacCallum Cancer Centre,
East Melbourne, Victoria, Australia; Department of Medicine, St Vincent/’s
Hospital, The University of Melbourne, Parkville, Victoria, Australia; Sir Peter
MacCallum Department of Oncology, The University of Melbourne, Parkville,
Victoria, Australia. <br />
INTRODUCTION: The Aurora kinases play a key role in mitosis and have recently
been identified as attractive targets for therapeutic intervention in cancer. The
aim of this study was therefore to investigate the utility of
3/’-[(18)F]fluoro-3/’-deoxythymidine (FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose
(FDG) for assessment of tumor response to the multi-targeted Aurora B kinase
inhibitor, TAK-901.<br />
METHODS: Balb/c nude mice bearing HCT116 colorectal xenografts were treated with
up to 30mg/kg TAK 901 or vehicle intravenously twice daily for two days on a
weekly cycle. Tumor growth was monitored by calliper measurements and PET imaging
was performed at baseline, day 4, 8, 11 and 15. Tumors were harvested at time
points corresponding to days of PET imaging for analysis of ex vivo markers of
cell proliferation and metabolism together with markers of Aurora B kinase
inhibition including phospho-histone H3 (pHH3) and senescence associated
β-galactosidase.<br />
RESULTS: Tumor growth was inhibited by 60% on day 12 of 30mg/kg TAK-901 therapy.
FLT uptake was significantly reduced by day 4 of treatment and this corresponded
with reduction in bromodeoxyuridine and pHH3 staining by immunohistochemistry.
All biomarkers rebounded towards baseline levels by the commencement of the next
treatment cycle, consistent with release of Aurora B kinase suppression. TAK-901
therapy had no impact on glucose metabolism as assessed by FDG uptake and GLUT1
staining by immunohistochemistry.<br />
CONCLUSIONS: FLT-PET, but not FDG-PET, is a robust non-invasive imaging biomarker
of early HCT116 tumor response to the on-target effects of the multi-targeted
Aurora B kinase inhibitor, TAK-901.
ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This is the first report
to demonstrate the impact of the multi-targeted Aurora B kinase inhibitor,
TAK-901 on tumor FLT uptake. The findings provide a strong rationale for the
evaluation of FLT-PET as an early biomarker of tumor response in the early phase
clinical development of this compound. <br />
3. Mol Cancer Ther. 2013 Apr;12(4):460-70. doi: 10.1158/1535-7163.MCT-12-0657. Epub
2013 Jan 28. <br />
Biological characterization of TAK-901, an investigational, novel, multitargeted
Aurora B kinase inhibitor. <br />
Farrell P(1), Shi L, Matuszkiewicz J, Balakrishna D, Hoshino T, Zhang L, Elliott
S, Fabrey R, Lee B, Halkowycz P, Sang B, Ishino S, Nomura T, Teratani M, Ohta Y,
Grimshaw C, Paraselli B, Satou T, de Jong R. <br />
Author information: <br />
(1)Discovery Biology, Takeda San Diego, Inc. 10410 Science Center Drive, San
Diego, CA 92121, USA. <br />
Protein kinases Aurora A, B, and C play essential roles during mitosis and cell
division, are frequently elevated in cancer, and represent attractive targets for
therapeutic intervention. TAK-901 is an investigational, multitargeted Aurora B
kinase inhibitor derived from a novel azacarboline kinase hinge-binder chemotype.
TAK-901 exhibited time-dependent, tight-binding inhibition of Aurora B, but not
Aurora A. Consistent with Aurora B inhibition, TAK-901 suppressed cellular
histone H3 phosphorylation and induced polyploidy. In various human cancer cell
lines, TAK-901 inhibited cell proliferation with effective concentration values
from 40 to 500 nmol/L. Examination of a broad panel of kinases in biochemical
assays revealed inhibition of multiple kinases. However, TAK-901 potently
inhibited only a few kinases other than Aurora B in intact cells, including FLT3
and FGFR2. In rodent xenografts, TAK-901 exhibited potent activity against
multiple human solid tumor types, and complete regression was observed in the
ovarian cancer A2780 model. TAK-901 also displayed potent activity against
several leukemia models. In vivo biomarker studies showed that TAK-901 induced
pharmacodynamic responses consistent with Aurora B inhibition and correlating
with retention of TAK-901 in tumor tissue. These preclinical data highlight the
therapeutic potential of TAK-901, which has entered phase I clinical trials in
patients within a diverse range of cancers. <br />
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