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Ref Type Journal Article
PMID (19741151)
Authors Jobson AG, Lountos GT, Lorenzi PL, Llamas J, Connelly J, Cerna D, Tropea JE, Onda A, Zoppoli G, Kondapaka S, Zhang G, Caplen NJ, Cardellina JH 2nd, Yoo SS, Monks A, Self C, Waugh DS, Shoemaker RH, Pommier Y
Title 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].
Journal The Journal of pharmacology and experimental therapeutics
Vol 331
Issue 3
Date 2009 Dec
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CCT241533 CCT241533 0 0
PV1019 PV1019 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PV1019 CHK2 Inhibitor 5 PV1019, a derivative of NSC109555, is an ATP-competitive inhibitor of CHK2, which leads to reduced CHK2 kinase activity and decreased tumor cell growth, and enhances the anti-tumor effects of chemotherapeutic agents (PMID: 19741151).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovarian cancer not applicable Camptothecin + PV1019 Preclinical - Cell culture Actionable In a preclinical study, treatment with PV1019 enhanced the anti-tumor effects of Camptothecin in ovarian cancer cells in culture, demonstrating greater growth inhibition (PMID: 19741151). 19741151
Unknown unknown malignant glioma not applicable PV1019 + Radiotherapy Preclinical - Cell culture Actionable In a preclinical study, glioma cells treated with PV1019 before and after radiotherapy resulted in greater cell death in culture than compared to radiation treatment alone (PMID: 19741151). 19741151
Unknown unknown ovarian cancer not applicable PV1019 + Topotecan Preclinical - Cell culture Actionable In a preclinical study, treatment with PV1019 combined with Hycamtin (topotecan) resulted in a synergistic effect, demonstrating greater growth inhibition of ovarian cancer cells in culture than when treated with Hycamtin (topotecan) alone (PMID: 19741151). 19741151