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PDBsum entry 2w7x
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References listed in PDB file
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Key reference
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Title
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Cellular inhibition of checkpoint kinase 2 (chk2) and potentiation of camptothecins and radiation by the novel chk2 inhibitor pv1019 [7-Nitro-1h-Indole-2-Carboxylic acid {4-[1-(Guanidinohydrazone)-Ethyl]-Phenyl}-Amide].
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Authors
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A.G.Jobson,
G.T.Lountos,
P.L.Lorenzi,
J.Llamas,
J.Connelly,
D.Cerna,
J.E.Tropea,
A.Onda,
G.Zoppoli,
S.Kondapaka,
G.Zhang,
N.J.Caplen,
J.H.Cardellina,
S.S.Yoo,
A.Monks,
C.Self,
D.S.Waugh,
R.H.Shoemaker,
Y.Pommier.
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Ref.
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J Pharmacol Exp Ther, 2009,
331,
816-826.
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PubMed id
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Abstract
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Chk2 is a checkpoint kinase involved in the ataxia telangiectasia mutated
pathway, which is activated by genomic instability and DNA damage, leading to
either cell death (apoptosis) or cell cycle arrest. Chk2 provides an unexplored
therapeutic target against cancer cells. We recently reported
4,4'-diacetyldiphenylurea-bis(guanylhydrazone) (NSC 109555) as a novel chemotype
Chk2 inhibitor. We have now synthesized a derivative of NSC 109555, PV1019 (NSC
744039) [7-nitro-1H-indole-2-carboxylic acid
{4-[1-(guanidinohydrazone)-ethyl]-phenyl}-amide], which is a selective
submicromolar inhibitor of Chk2 in vitro. The cocrystal structure of PV1019
bound in the ATP binding pocket of Chk2 confirmed enzymatic/biochemical
observations that PV1019 acts as a competitive inhibitor of Chk2 with respect to
ATP. PV1019 was found to inhibit Chk2 in cells. It inhibits Chk2
autophosphorylation (which represents the cellular kinase activation of Chk2),
Cdc25C phosphorylation, and HDMX degradation in response to DNA damage. PV1019
also protects normal mouse thymocytes against ionizing radiation-induced
apoptosis, and it shows synergistic antiproliferative activity with topotecan,
camptothecin, and radiation in human tumor cell lines. We also show that PV1019
and Chk2 small interfering RNAs can exert antiproliferative activity themselves
in the cancer cells with high Chk2 expression in the NCI-60 screen. These data
indicate that PV1019 is a potent and selective inhibitor of Chk2 with
chemotherapeutic and radiosensitization potential.
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