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PDBsum entry 2w0j
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References listed in PDB file
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Key reference
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Title
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Crystal structure of checkpoint kinase 2 in complex with nsc 109555, A potent and selective inhibitor.
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Authors
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G.T.Lountos,
J.E.Tropea,
D.Zhang,
A.G.Jobson,
Y.Pommier,
R.H.Shoemaker,
D.S.Waugh.
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Ref.
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Protein Sci, 2009,
18,
92-100.
[DOI no: ]
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PubMed id
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Abstract
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Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint
pathway, is activated by genomic instability and DNA damage and results in
either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the
DNA damage is severe. Drugs that specifically target Chk2 could be beneficial
when administered in combination with current DNA-damaging agents used in cancer
therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that
exhibited high potency (IC(50) = 240 nM) and selectivity. This compound
represents a new chemotype and lead for the development of novel Chk2 inhibitors
that could be used as therapeutic agents for the treatment of cancer. To
facilitate the discovery of new analogs of NSC 109555 with even greater potency
and selectivity, we have solved the crystal structure of this inhibitor in
complex with the catalytic domain of Chk2. The structure confirms that the
compound is an ATP-competitive inhibitor, as the electron density clearly
reveals that it occupies the ATP-binding pocket. However, the mode of inhibition
differs from that of the previously studied structure of Chk2 in complex with
debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique
hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents
an opportunity for the rational design of compounds with higher binding affinity
and greater selectivity.
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Figure 1.
A: Chemical structure of NSC 109555. B: The coordinates of
NSC 109555 superimposed on the final 2F[o] [minus sign] F[c]
electron density maps at 2.05 A resolution contoured at the
1[sigma] level.
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Figure 5.
An overlay of the coordinates of the Chk2-NSC 109555 (PDB
code: 2W0J), Chk2-ADP (PDB code: 2CN5), and Chk2-DBQ (PDB code:
2CN8) crystal structures comparing the orientations of NSC
109555 (blue stick), ADP (orange stick), and DBQ (purple stick)
in the ATP-binding pocket of Chk2 (green stick). The coordinates
for the amino acid side chains are for the refined model of Chk2
in complex with NSC 109555.
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(2009,
18,
92-100)
copyright 2009.
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Secondary reference #1
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Title
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Identification of a bis-Guanylhydrazone [4,4'-Diacetyldiphenylurea-Bis(guanylhydrazone); nsc 109555] as a novel chemotype for inhibition of chk2 kinase.
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Authors
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A.G.Jobson,
J.H.Cardellina,
D.Scudiero,
S.Kondapaka,
H.Zhang,
H.Kim,
R.Shoemaker,
Y.Pommier.
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Ref.
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Mol Pharmacol, 2007,
72,
876-884.
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PubMed id
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