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PDBsum entry 2x81
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References listed in PDB file
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Key reference
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Title
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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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Authors
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D.A.Sloane,
M.Z.Trikic,
M.L.Chu,
M.B.Lamers,
C.S.Mason,
I.Mueller,
W.J.Savory,
D.H.Williams,
P.A.Eyers.
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Ref.
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Acs Chem Biol, 2010,
5,
563-576.
[DOI no: ]
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PubMed id
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Abstract
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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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