| Reference | 1. ACS Chem Biol. 2010 Jun 18;5(6):563-76. doi: 10.1021/cb100053q.
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Drug-resistant aurora A mutants for cellular target validation of the small
molecule kinase inhibitors MLN8054 and MLN8237.
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Sloane DA(1), Trikic MZ, Chu ML, Lamers MB, Mason CS, Mueller I, Savory WJ,
Williams DH, Eyers PA.
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Author information: <br>
(1)Yorkshire Cancer Research Institute for Cancer Studies, University of
Sheffield, UK.
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The Aurora kinases regulate multiple aspects of mitotic progression, and their
overexpression in diverse tumor types makes them appealing oncology targets. An
intensive research effort over the past decade has led to the discovery of
chemically distinct families of small molecule Aurora kinase inhibitors, many of
which have demonstrated therapeutic potential in model systems. These agents are
also important tools to help dissect signaling pathways that are orchestrated by
Aurora kinases, and the antiproliferative target of pan-Aurora inhibitors such as
VX-680 has been validated using chemical genetic techniques. In many cases the
nonspecific nature of Aurora inhibitors toward unrelated kinases is well
established, potentially broadening the spectrum of cancers to which these
compounds might be applied. However, unambiguously demonstrating the molecular
target(s) for clinical kinase inhibitors is an important challenge, one that is
absolutely critical for deciphering the molecular basis of compound specificity,
resistance, and efficacy. In this paper, we have investigated amino acid
requirements for Aurora A sensitivity to the benzazepine-based Aurora inhibitor
MLN8054 and the close analogue MLN8237, a second-generation compound that is in
phase II clinical trials. A crystallographic analysis facilitated the design and
biochemical investigation of a panel of resistant Aurora A mutants, a subset of
which were then selected as candidate drug-resistance targets for further
evaluation. Using inducible human cell lines, we show that cells expressing
near-physiological levels of a functional but partially drug-resistant Aurora A
T217D mutant survive in the presence of MLN8054 or MLN8237, authenticating Aurora
A as a critical antiproliferative target of these compounds.
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2. Mol Cancer Res. 2010 Mar;8(3):373-84. doi: 10.1158/1541-7786.MCR-09-0300. Epub
2010 Mar 2.
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MLN8054, an inhibitor of Aurora A kinase, induces senescence in human tumor cells
both in vitro and in vivo.
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Huck JJ(1), Zhang M, McDonald A, Bowman D, Hoar KM, Stringer B, Ecsedy J,
Manfredi MG, Hyer ML.
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Author information: <br>
(1)Millennium Pharmaceuticals, Cambridge, MA 02139, USA.
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Aurora A kinase is a serine/threonine protein kinase responsible for regulating
several mitotic processes including centrosome separation, spindle assembly, and
chromosome segregation. Small molecule inhibitors of Aurora A kinase are being
pursued as novel anticancer agents, some of which have entered clinical trials.
Despite the progress in developing these agents, terminal outcomes associated
with Aurora A inhibition are not fully understood. Although evidence exists that
Aurora A inhibition leads to apoptosis, other therapeutically relevant cell fates
have not been reported. Here, we used the small molecule inhibitor MLN8054 to
show that inhibition of Aurora A induces tumor cell senescence both in vitro and
in vivo. Treatment of human tumor cells grown in culture with MLN8054 showed a
number of morphologic and biochemical changes associated with senescence. These
include increased staining of senescence-associated beta-galactosidase, increased
nuclear and cell body size, vacuolated cellular morphology,
upregulation/stabilization of p53, p21, and hypophosphorylated pRb. To determine
if Aurora A inhibition induces senescence in vivo, HCT-116 xenograft-bearing
animals were dosed orally with MLN8054 for 3 weeks. In the MLN8054-treated
animals, increased senescence-associated beta-galactosidase activity was detected
in tissue sections starting on day 15. In addition, DNA and tubulin staining of
tumor tissue showed a significant increase in nuclear and cell body area,
consistent with a senescent phenotype. Taken together, this data shows that
senescence is a terminal outcome of Aurora A inhibition and supports the
evaluation of senescence biomarkers in clinic samples.
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3. Mol Cell Biol. 2007 Jun;27(12):4513-25. Epub 2007 Apr 16.
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MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and
chromosome congression defects leading to aneuploidy.
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Hoar K(1), Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N, Ecsedy JA.
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Author information: <br>
(1)Department of Molecular and Cellular Oncology, Millenium Pharmaceuticals Inc,
Cambridge, MA 02139, USA.
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Aurora A kinase plays an essential role in the proper assembly and function of
the mitotic spindle, as its perturbation causes defects in centrosome separation,
spindle pole organization, and chromosome congression. Moreover, Aurora A
disruption leads to cell death via a mechanism that involves aneuploidy
generation. However, the link between the immediate functional consequences of
Aurora A inhibition and the development of aneuploidy is not clearly defined. In
this study, we delineate the sequence of events that lead to aneuploidy following
Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor.
Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic
spindles, often with unseparated centrosomes. Although these spindle defects
result in mitotic delays, cells ultimately divide at a frequency near that of
untreated cells. We show that many of the spindles in the dividing cells are
bipolar, although they lack centrosomes at one or more spindle poles.<br>
MLN8054-treated cells frequently show alignment defects during metaphase, lagging
chromosomes in anaphase, and chromatin bridges during telophase. Consistent with
the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy
over time. Taken together, these results suggest that Aurora A inhibition kills
tumor cells through the development of deleterious aneuploidy.
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4. Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4106-11. Epub 2007 Feb 23.
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Antitumor activity of MLN8054, an orally active small-molecule inhibitor of
Aurora A kinase.
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Manfredi MG(1), Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM,
Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ,
Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF.
<br>
Author information: <br>
(1)Department of Oncology, Millennium Pharmaceuticals Inc., 40 Landsdowne Street,
Cambridge, MA 02139, USA. [email protected]
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Increased Aurora A expression occurs in a variety of human cancers and induces
chromosomal abnormalities during mitosis associated with tumor initiation and
progression. MLN8054 is a selective small-molecule Aurora A kinase inhibitor that
has entered Phase I clinical trials for advanced solid tumors. MLN8054 inhibits
recombinant Aurora A kinase activity in vitro and is selective for Aurora A over
the family member Aurora B in cultured cells. MLN8054 treatment results in G(2)/M
accumulation and spindle defects and inhibits proliferation in multiple cultured
human tumor cells lines. Growth of human tumor xenografts in nude mice was
dramatically inhibited after oral administration of MLN8054 at well tolerated
doses. Moreover, the tumor growth inhibition was sustained after discontinuing
MLN8054 treatment. In human tumor xenografts, MLN8054 induced mitotic
accumulation and apoptosis, phenotypes consistent with inhibition of Aurora A.
MLN8054 is a selective inhibitor of Aurora A kinase that robustly inhibits growth
of human tumor xenografts and represents an attractive modality for therapeutic
intervention of human cancers.
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