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PDBsum entry 2qi8
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Signaling protein, transferase
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PDB id
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2qi8
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References listed in PDB file
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Key reference
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Title
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Structural insights into how irreversible inhibitors can overcome drug resistance in egfr.
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Authors
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A.Michalczyk,
S.Klüter,
H.B.Rode,
J.R.Simard,
C.Grütter,
M.Rabiller,
D.Rauh.
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Ref.
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Bioorg Med Chem Lett, 2008,
16,
3482-3488.
[DOI no: ]
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PubMed id
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Abstract
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Resistance to kinase-targeted cancer drugs has recently been linked to a single
point mutation in the ATP binding site of the kinase. In EGFR, the crucial
Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP
competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines
have been shown to overcome this drug resistance and are currently in clinical
trials. In order to obtain a detailed structural understanding of how
irreversible inhibitors overcome drug resistance, we used Src kinase as a model
system for drug resistant EGFR-T790M. We report the first crystal structure of a
drug resistant kinase in complex with an irreversible inhibitor. This
4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro
at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M
kinase domain provides the structural basis of this activity.
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