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PDBsum entry 3w2q
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Transferase/transferase inhibitor
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PDB id
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3w2q
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References listed in PDB file
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Key reference
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Title
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Structure-Based approach for the discovery of pyrrolo[3,2-D]pyrimidine-Based egfr t790m/l858r mutant inhibitors.
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Authors
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S.Sogabe,
Y.Kawakita,
S.Igaki,
H.Iwata,
H.Miki,
D.R.Cary,
T.Takagi,
S.Takagi,
Y.Ohta,
T.Ishikawa.
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Ref.
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ACS Med Chem Lett, 2013,
4,
201-205.
[DOI no: ]
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PubMed id
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Abstract
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The epidermal growth factor receptor (EGFR) family plays a critical role in
vital cellular processes and in various cancers. Known EGFR inhibitors exhibit
distinct antitumor responses against the various EGFR mutants associated with
nonsmall-cell lung cancer. The L858R mutation enhances clinical sensitivity to
gefitinib and erlotinib as compared with wild type and reduces the relative
sensitivity to lapatinib. In contrast, the T790M mutation confers drug
resistance to gefitinib and erlotinib. We determined crystal structures of the
wild-type and T790M/L858R double mutant EGFR kinases with reversible and
irreversible pyrrolo[3,2-d]pyrimidine inhibitors based on analogues of TAK-285
and neratinib. In these structures, M790 adopts distinct conformations to
accommodate different inhibitors, whereas R858 allows conformational variations
of the activation loop. These results provide structural insights for
understanding the structure-activity relationships that should contribute to the
development of potent inhibitors against drug-sensitive or -resistant EGFR
mutations.
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