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PDBsum entry 4i4e
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Transferase/transferase inhibitor
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PDB id
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4i4e
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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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Structure of focal adhesion kinase catalytic domain in complex with hinge binding pyrazolobenzothiazine compound.
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Structure:
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Focal adhesion kinase 1. Chain: a. Fragment: kinase domain: unp residues 411-686. Synonym: fadk 1, focal adhesion kinase-related nonkinase, frnk, protein phosphatase 1 regulatory subunit 71, ppp1r71, protein- tyrosine kinase 2, p125fak, pp125fak. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ptk2, fak, fak1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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1.55Å
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R-factor:
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0.166
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R-free:
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0.189
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Authors:
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R.J.Skene,D.J.Hosfield
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Key ref:
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N.Tomita
et al.
(2013).
Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg Med Chem Lett,
23,
1779-1785.
PubMed id:
DOI:
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Date:
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27-Nov-12
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Release date:
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06-Mar-13
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PROCHECK
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Headers
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References
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Q05397
(FAK1_HUMAN) -
Focal adhesion kinase 1 from Homo sapiens
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Seq:
Struc:
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1052 a.a.
254 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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Enzyme class:
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E.C.2.7.10.2
- non-specific 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
23:1779-1785
(2013)
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PubMed id:
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Structure-based discovery of cellular-active allosteric inhibitors of FAK.
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N.Tomita,
Y.Hayashi,
S.Suzuki,
Y.Oomori,
Y.Aramaki,
Y.Matsushita,
M.Iwatani,
H.Iwata,
A.Okabe,
Y.Awazu,
O.Isono,
R.J.Skene,
D.J.Hosfield,
H.Miki,
T.Kawamoto,
A.Hori,
A.Baba.
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ABSTRACT
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In order to develop potent and selective focal adhesion kinase (FAK) inhibitors,
synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK
allosteric site were carried out. Based on the X-ray structural analysis of the
co-crystal of the lead compound,
8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine
4,4-dioxide 1 with FAK, we designed and prepared
1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which
selectively inhibited kinase activity of FAK without affecting seven other
kinases. The optimized compound,
N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine
4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in
cell-free (IC=0.64μM) and in cellular assays (IC=7.1μM). These results clearly
demonstrated a potential of FAK allosteric inhibitors as antitumor agents.
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