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PDBsum entry 3rcd
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Transferase/transferase inhibitor
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PDB id
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3rcd
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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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Her2 kinase domain complexed with tak-285
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Structure:
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Receptor tyrosine-protein kinase erbb-2. Chain: a, b, c, d. Fragment: unp residues 713-1028. Synonym: metastatic lymph node gene 19 protein, mln 19, proto- oncogene neu, proto-oncogenE C-erbb-2, tyrosine kinase-type cell surface receptor her2, p185erbb2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: erbb2, her2, mln19, neu, ngl. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
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Resolution:
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3.21Å
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R-factor:
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0.227
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R-free:
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0.294
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Authors:
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K.Aertgeerts,R.Skene,S.Sogabe
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Key ref:
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T.Ishikawa
et al.
(2011).
Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold.
J Med Chem,
54,
8030-8050.
PubMed id:
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Date:
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30-Mar-11
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Release date:
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23-Nov-11
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PROCHECK
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Headers
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References
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P04626
(ERBB2_HUMAN) -
Receptor tyrosine-protein kinase erbB-2 from Homo sapiens
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Seq:
Struc:
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1255 a.a.
281 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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J Med Chem
54:8030-8050
(2011)
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PubMed id:
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Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold.
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T.Ishikawa,
M.Seto,
H.Banno,
Y.Kawakita,
M.Oorui,
T.Taniguchi,
Y.Ohta,
T.Tamura,
A.Nakayama,
H.Miki,
H.Kamiguchi,
T.Tanaka,
N.Habuka,
S.Sogabe,
J.Yano,
K.Aertgeerts,
K.Kamiyama.
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ABSTRACT
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Dual inhibitors of human epidermal growth factor receptor 2 (HER2) and epidermal
growth factor receptor (EGFR) have been investigated for breast, lung, gastric,
prostate, and other cancers; one, lapatinib, is currently approved for breast
cancer. To develop novel HER2/EGFR dual kinase inhibitors, we designed and
synthesized pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the
receptors' ATP binding site. Among the prepared compounds, 34e showed potent
HER2 and EGFR (HER1) inhibitory activities as well as tumor growth inhibitory
activity. The X-ray cocrystal structures of 34e with both HER2 and EGFR
demonstrated that 34e interacts with the expected residues in their respective
ATP pockets. Furthermore, reflecting its good oral bioavailability, 34e
exhibited potent in vivo efficacy in HER2-overexpressing tumor xenograft models.
On the basis of these findings, we report 34e (TAK-285) as a promising candidate
for clinical development as a novel HER2/EGFR dual kinase inhibitor.
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Links
