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PDBsum entry 5edr
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Transferase/transferase inhibitor
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PDB id
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5edr
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Egfr kinase (t790m/l858r) with inhibitor compound 27: ~{n}-(1~{h}- indazol-3-yl)-7,7-dimethyl-2-(2-methylpyrazol-3-yl)-5~{h}-furo[3,4- d]pyrimidin-4-amine
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Structure:
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Epidermal growth factor receptor. Chain: a. Synonym: proto-oncogenE C-erbb-1,receptor tyrosine-protein kinase erbb-1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: egfr, erbb, erbb1, her1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.60Å
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R-factor:
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0.192
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R-free:
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0.215
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Authors:
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C.Eigenbrot,C.Yu
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Key ref:
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E.J.Hanan
et al.
(2016).
4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.
Bioorg Med Chem Lett,
26,
534-539.
PubMed id:
DOI:
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Date:
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21-Oct-15
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Release date:
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02-Dec-15
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PROCHECK
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Headers
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References
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P00533
(EGFR_HUMAN) -
Epidermal growth factor receptor from Homo sapiens
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Seq:
Struc:
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1210 a.a.
299 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Bioorg Med Chem Lett
26:534-539
(2016)
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PubMed id:
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4-Aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of mutant epidermal growth factor receptor tyrosine kinase.
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E.J.Hanan,
M.Baumgardner,
M.C.Bryan,
Y.Chen,
C.Eigenbrot,
P.Fan,
X.H.Gu,
H.La,
S.Malek,
H.E.Purkey,
G.Schaefer,
S.Schmidt,
S.Sideris,
I.Yen,
C.Yu,
T.P.Heffron.
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ABSTRACT
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The treatment of epidermal growth factor receptor (EGFR)-driven non-small cell
lung cancers with the T790M resistance mutation remains a significant unmet
medical need. We report the identification of
4-aminoindazolyl-dihydrofuro[3,4-d]pyrimidines as non-covalent inhibitors of
EGFR, with excellent activity against the T790M resistance double mutants and
initial single activating mutants. Using an optimization strategy focused on
structure-based design and improving PK properties through metabolite
identification, we obtained advanced leads with high oral exposure.
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Links
