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PDBsum entry 2xf0
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Contents |
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of checkpoint kinase 1 (chk1) in complex with inhibitors
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Structure:
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Serine/threonine-protein kinase chk1. Chain: a. Fragment: kinase domain, residues 1-289. Synonym: checkpoint kinase 1, chek1, chk1. Engineered: yes
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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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2.40Å
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R-factor:
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0.205
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R-free:
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0.244
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Authors:
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T.P.Matthews,T.Mchardy,S.Klair,K.Boxall,M.Fisher,M.Cherry,C.E.Allen, G.J.Addison,J.Ellard,G.W.Aherne,I.M.Westwood,R.Van Montfort, M.D.Garrett,J.C.Reader,I.Collins
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Key ref:
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T.P.Matthews
et al.
(2010).
Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.
Bioorg Med Chem Lett,
20,
4045-4049.
PubMed id:
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Date:
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19-May-10
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Release date:
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30-Jun-10
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PROCHECK
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Headers
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References
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O14757
(CHK1_HUMAN) -
Serine/threonine-protein kinase Chk1 from Homo sapiens
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Seq:
Struc:
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476 a.a.
251 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.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[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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Bioorg Med Chem Lett
20:4045-4049
(2010)
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PubMed id:
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Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases.
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T.P.Matthews,
T.McHardy,
S.Klair,
K.Boxall,
M.Fisher,
M.Cherry,
C.E.Allen,
G.J.Addison,
J.Ellard,
G.W.Aherne,
I.M.Westwood,
R.van Montfort,
M.D.Garrett,
J.C.Reader,
I.Collins.
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ABSTRACT
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A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors
of CHK1 were developed by scaffold hopping from a weakly active screening hit.
Efficient synthetic routes for parallel synthesis were developed to prepare
analogues with improved potency and ligand efficiency against CHK1. Kinase
profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases,
including CHK2 and ABL, with equivalent or better potency depending on the
pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to
represent a general kinase inhibitor scaffold.
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Links
