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PDBsum entry 4ccb
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PDB id:
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Transferase
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Title:
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Structure of the human anaplastic lymphoma kinase in complex with 3- ((r)-1-(5-fluoro-2-(2h-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(5-methyl- 1h- pyrazol-4-yl)pyridin-2-amine
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Structure:
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Alk tyrosine kinase receptor. Chain: a. Fragment: tyrosine kinase domain, residues 1093-1411. Synonym: anaplastic lymphoma kinase, anaplastic lymphoma kinase. Engineered: yes. Other_details: nonphosphorylated
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
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Resolution:
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2.03Å
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R-factor:
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0.202
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R-free:
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0.235
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Authors:
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M.Mctigue,Y.Deng,W.Liu,A.Brooun,A.Stewart
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Key ref:
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Q.Huang
et al.
(2014).
Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
J Med Chem,
57,
1170-1187.
PubMed id:
DOI:
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Date:
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21-Oct-13
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Release date:
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29-Jan-14
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PROCHECK
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Headers
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References
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Q9UM73
(ALK_HUMAN) -
ALK tyrosine kinase receptor from Homo sapiens
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Seq:
Struc:
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1620 a.a.
291 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.2.7.10.1
- 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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J Med Chem
57:1170-1187
(2014)
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PubMed id:
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Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib.
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Q.Huang,
T.W.Johnson,
S.Bailey,
A.Brooun,
K.D.Bunker,
B.J.Burke,
M.R.Collins,
A.S.Cook,
J.J.Cui,
K.N.Dack,
J.G.Deal,
Y.L.Deng,
D.Dinh,
L.D.Engstrom,
M.He,
J.Hoffman,
R.L.Hoffman,
P.S.Johnson,
R.S.Kania,
H.Lam,
J.L.Lam,
P.T.Le,
Q.Li,
L.Lingardo,
W.Liu,
M.W.Lu,
M.McTigue,
C.L.Palmer,
P.F.Richardson,
N.W.Sach,
H.Shen,
T.Smeal,
G.L.Smith,
A.E.Stewart,
S.Timofeevski,
K.Tsaparikos,
H.Wang,
H.Zhu,
J.Zhu,
H.Y.Zou,
M.P.Edwards.
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ABSTRACT
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Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase
inhibitor approved by the U.S. Food and Drug Administration in 2011, is
efficacious in ALK and ROS positive patients. Under pressure of crizotinib
treatment, point mutations arise in the kinase domain of ALK, resulting in
resistance and progressive disease. The successful application of both
structure-based and lipophilic-efficiency-focused drug design resulted in
aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant
cell lines and showed suitable preclinical pharmacokinetics and robust tumor
growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).
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