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PDBsum entry 2vrx
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Cell cycle/transferase
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PDB id
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2vrx
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References listed in PDB file
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Key reference
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Title
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Molecular basis of drug resistance in aurora kinases.
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Authors
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F.Girdler,
F.Sessa,
S.Patercoli,
F.Villa,
A.Musacchio,
S.Taylor.
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Ref.
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Chem Biol, 2008,
15,
552-562.
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PubMed id
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Abstract
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Aurora kinases have emerged as potential targets in cancer therapy, and several
drugs are currently undergoing preclinical and clinical validation. Whether
clinical resistance to these drugs can arise is unclear. We exploited a
hypermutagenic cancer cell line to select mutations conferring resistance to a
well-studied Aurora inhibitor, ZM447439. All resistant clones contained dominant
point mutations in Aurora B. Three mutations map to residues in the ATP-binding
pocket that are distinct from the "gatekeeper" residue. The mutants
retain wild-type catalytic activity and were resistant to all of the Aurora
inhibitors tested. Our studies predict that drug-resistant Aurora B mutants are
likely to arise during clinical treatment. Furthermore, because the plasticity
of the ATP-binding pocket renders Aurora B insensitive to multiple inhibitors,
our observations indicate that the drug-resistant Aurora B mutants should be
exploited as novel drug targets.
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