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Ref Type Journal Article
PMID (21730979)
Authors Peasland A, Wang LZ, Rowling E, Kyle S, Chen T, Hopkins A, Cliby WA, Sarkaria J, Beale G, Edmondson RJ, Curtin NJ
Title Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines.
Journal British journal of cancer
Vol 105
Issue 3
Date 2011 Jul 26
URL
Abstract Text The ataxia telangiectasia mutated and Rad3-related kinase (ATR) has a key role in the signalling of stalled replication forks and DNA damage to cell cycle checkpoints and DNA repair. It has long been recognised as an important target for cancer therapy but inhibitors have proved elusive. As NU6027, originally developed as a CDK2 inhibitor, potentiated cisplatin in a CDK2-independent manner we postulated that it may inhibit ATR.Cellular ATR kinase activity was determined by CHK1 phosphorylation in human fibroblasts with inducible dominant-negative ATR-kinase dead expression and human breast cancer MCF7 cells. Cell cycle effects and chemo- and radiopotentiation by NU6027 were determined in MCF7 cells and the role of mismatch repair and p53 was determined in isogenically matched ovarian cancer A2780 cells.NU6027 is a potent inhibitor of cellular ATR activity (IC(50)=6.7 μM) and enhanced hydroxyurea and cisplatin cytotoxicity in an ATR-dependent manner. NU6027 attenuated G2/M arrest following DNA damage, inhibited RAD51 focus formation and increased the cytotoxicity of the major classes of DNA-damaging anticancer cytotoxic therapy but not the antimitotic, paclitaxel. In A2780 cells sensitisation to cisplatin was greatest in cells with functional p53 and mismatch repair (MMR) and sensitisation to temozolomide was greatest in p53 mutant cells with functional MMR. Importantly, NU6027 was synthetically lethal when DNA single-strand break repair is impaired either through poly(ADP-ribose) polymerase (PARP) inhibition or defects in XRCC1.NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors. It provides proof of concept data for clinical development of ATR inhibitors.

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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
NU6027 NU6027 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
NU6027 ATR Inhibitor 10 CDK2 Inhibitor 19 NU6027 is a small molecule inhibitor of ATR and CDK2, which may enhance the sensitivity of chemotherapeutic agents and result in decreased cell survival (PMID: 21730979, PMID: 27355194).
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 breast cancer not applicable Doxorubicin + NU6027 Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Adriamycin (doxorubicin) in breast cancer cells in culture, resulting in decreased cell survival (PMID: 21730979). 21730979
Unknown unknown breast cancer not applicable Cisplatin + NU6027 Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Platinol (cisplatin) in breast cancer cells in culture, resulting in decreased cell survival (PMID: 21730979). 21730979
Unknown unknown breast cancer not applicable NU6027 + Rucaparib Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Rubraca (rucaparib) in breast cancer cells in culture, resulting in a greater decreased cell survival (PMID: 21730979). 21730979
Unknown unknown breast cancer not applicable Hydroxyurea + NU6027 Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Droxia (hydroxyurea) in breast cancer cells in culture, resulting in decreased cell survival (PMID: 21730979). 21730979
Unknown unknown ovarian cancer not applicable Cisplatin + NU6027 Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Platinol (cisplatin) in ovarian cancer cells in culture, resulting in decreased cell survival (PMID: 21730979). 21730979
Unknown unknown breast cancer not applicable Camptothecin + NU6027 Preclinical - Cell culture Actionable In a preclinical study, NU6027 enhanced the efficacy of Camptothecin in breast cancer cells in culture, resulting in decreased cell survival (PMID: 21730979). 21730979