Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer	105	3	2011 Jul 26	372-81	Br J Cancer

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 16 CDK2 Inhibitor 31	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
TP53 positive	ovarian cancer	predicted - sensitive	NU6027 + Temozolomide	Preclinical - Cell culture	Actionable	In a preclinical study, NU6027 enhanced the efficacy of Temodar (temozolomide) in ovarian cancer cells with mismatch repair activity and positive for TP53 in culture, demonstrating a 50% greater decrease in cell survival compared to Temodar (temozolomide) alone (PMID: 21730979).	21730979